Types systemic Therapy
-Anti-hormonal therapy
-Targeted therapy
-Radiotherapy: Targeted isotopes
Chemotherapy (Goals)
1.) To cure malignancies:
-Childhood ALL
-Hodgkin’s disease
-Testicular cancer2. to improve cure rates (adjuvant therapy):
-Breast cancer
-Colon cancer
-Lung cancer
-Bladder cancer

3. to spare organ function (along with radiation):
-Larynx cancer
-Lung cancer
-Anal cancer

4. To extend life (not necessarily cure):

5. to palliate symptoms (Less unpleasant):
-Most malignancies

Chemotherapy (Principles)
1.) *Principle of log kill*
-A clinically detectable tumor has a mass of approximately 1 gram= 1,000,000,000 cells (possibly less)
-1+ kg tumor is usually lethal
-In theory effectively dosed chemo kills a CONSTANT FRACTION of cancer cells-Subsequent doses kill a similar fraction of remaining cancer cells
-1st order kinetics

2.) *Death of residual cancer cells requires other mechanisms*
-Possibly immunologic
-Possibly apoptosis: Programmed cell death

3.) *Absolute cancer irradication by chemotherapy may NOT occur*
-Extremely late recurrences of chemotherapy treated cancers seen
-Ex.) Hodgkin’s Disease, breast cancer, etc.

Chemotherapy (Cycling)

Chemotherapy is most ACTIVE if cells are replicating= *CYCLING*

-Most tumors actually have a SMALL percentage of cells CYCLING

>Prostate Cancer: 1-3% (low cycling)

>Breast Cancer: 1-10%

>Colon Cancer: 2-5%

>Lymphoma: 10-25%

>Leukemia: 50-90% (high cycling)

Control of Cell Cycle
Control of Cell Cycle

-From Go (resting) cell enters G1

-Most active phase is G1 then S
>Several drugs act at these highly active stages (G1 and S)
>If drug acts only on G1: it’s considered *cell cycle specific*

>If drug acts on several stages, then it is considered *non-specific*

-Few act on G0, G2, and M phases

Cell cycle specific vs cell cycle non-specific
Certain types of chemotherapeutic agents require cells to be *cycling to be active*
-CELL CYCLE SPECIFIC-> Anti-metabolites (Methotrexate, etc)Other types of chemo are active INDEPENDENT of whether cells are cycling or not (although MORE active if cycling)-> direct DNA damage
– CELL CYCLE NON-SPECIFIC-> Alkylators (analogous to radiation therapy)

Cell Cycle and CDKs

Each transition in the cell cycle is controlled by *cyclin dependent kinases (CDK’s)*-> activated by corresponding regulating proteins called *cyclins*

-INHIBITED by proteins such as *p16* ( 16-kilodalton) from multiple tumor suppressor gene: *1(MTS-1)*

-Mutation or loss of p16 (from chromosome 9) can result in relentless proliferation of cancer cells-> *Retinoblastoma*

-In contrast good prognosis HPV associated head and neck cancers OVEREXPRESS p16.

Cells with damaged DNA undergo apoptosis via…

Cells with DAMAGED DNA usually undergo apoptosis which is controlled to a degree by normal *p53 protein* (53 – kilodalton).

-Mutation or loss of p53 (from chromosome 17) activity can also lead to uncontrolled tumor growth-> *Li-Fraumeni syndrome*

Gompertzian growth
Gompertzian growth

-As tumors grow their growth fraction (GF) may DECREASE due to factors such as HYPOXIC conditions

-Conversely as tumors shrink their growth fraction may INCREASE making them more susceptible to chemotherapy= more cycling cells

-Small tumors more responsive to chemo

-Large tumors less responsive

-Harder to kill with more time and cells have reached peak number-> dividing less

Gompertz tumor growth curve
Gompertz tumor growth curve

At one point of mass growth: there is LACK of blood supply to the center-> size of the mass DECREASES

-Until a certain point, during log phase, cancer cannot be detected

-If cannot be identified early on: Can be wiped out with Ab
Irradiation or chemo

P16 and Rb

-p16 is from chromosome 9

-Rb gene is from chromosome 13

-p16 decelerates progression from G1 to S-phase
>INHIBITS cyclin dependent kinase 4 and 6 (CDK 4 and 6) preventing phosphorylation of Rb protein=PREVENTING progression from G1 to S

Alkylating Agent

Alkane: An open chain hydrocarbon containing primarily carbon to carbon or carbon to hydrogen single bonds

Alkyl group: An alkane missing one hydrogen
-typically part of a larger molecule
-Very reactive: unpaired electron=*electrophilic*

-Forms ADDUCTS with nucleophilic molecules

*Cell Cycle NON Specific*

Nitrogen Mustards
Nitrogen Mustards
*Specificity for N7 position of guanine*-When chlorine leaves-> mustard becomes very ACTIVE and binds to DNA


Alkylators (Common Properties)

1.) Act through covalent bonding of alkyl group(s) to intracellular macromolecules:

-Generate HIGHLY reactive positively charged intermediates

-Combine with electron-rich “*nucleophilic*” groups such as amino, phosphate, sulfhydryl, or hydroxyl moieties

-May contain one or two functional groups (monofunctional or bifunctional) .

2.) Alkylation of DNA bases appears to be major cause of lethal toxicity to cancer cells: *N7 position of guanine*

3.) Monofunctional: SINGLE strand breaks

4.) Bifunctional: Cross linking

5.) *Toxicity worse in cells deficient in DNA repair enzymes*
Ex.) *Ataxia telangiectasia syndrome*

6. *Secondary malignancies* such as *AML* is most COMMON
due to DNA damage WITHOUT cell death

Alkylation of DNA guanine (Mechanism)
Alkylation of DNA guanine (Mechanism)
Alkylation of DNA guanine (N7)= Alkylated purine
-When two alkylations occur from same alkylator= cross linking of DNA strands-Breaks in DNA-> no longer divide

*Nitrogen mustards form reactive ethyleneimmonium and carbonium ions-> attack nucleophilic groups especially the N-7 position of guanine*

Nitrosoureas Alkylators
Nitrosoureas Alkylators
-A class of alkylating-like agents that include both a *nitroso group (R-NO) and a urea*
-Not classic alkylators but work similarly-Covalently bind with nucleic acids

-Cause cross linking

-FAT soluble: Can cross Blood Brain Barrier

-*PROLONGED bone marrow suppression*

Ex.) Carbmustine,Lomustine, and Semustine (-mustine)

Other Alkylators
-Busulfan: Was used for CML, but caused pulmonary toxicity-> Imatinib/Gleevec has taken over
-Procarbazine (Mutalane)
-Dacarbazine (DTIC)
-Temozolamide-Don’t look like typical alkylators but all have a REACTIVE intermediate that has alkylating function
Ex.) Unpaired electron

-Used for Hodgkin’s Disease and brain tumorMustard that has *Antabuse (disulfiram)* effect when used with alcohol
>Inhibits ADH-> Acetaldehyde stays longer in body-> toxic

-Hydrazine derivative: coupling of pair of ammonia molecules by removal of one hydrogen per molecule

*Antabuse effect*



-Active in Rx of *metastatic melanoma*
(so is Ipilimumab and Vumrafenib)

-Being replaced by bRAF inhibitors and mAbs.

-Triazine derivative: Aromatic ring with 3 nitrogen atoms


*Crosses BBB*

-Improves survival in *gliomas* when used in combination with RADIATION therapy

-Oral prodrug similar to DTIC

-Tetrazine derivative: aromatic ring with 4 hydrogen atoms

*Most useful in reaction of GLIOMAS*

Alkylators (Resistance)

-DECREASED intracellular accumulation of drug: Amplification of gene responsible for *trans membrane efflux* (possibly MDR gene)

-Increased intracellular thiol (Ex: *Glutathione*) concentration via gene amplification
>A thiol is an organosulfur compound that can neutralize alkylation

-*Change in DNA repair enzymes: Gene amplification
>Amount of enzyme or efficiency (mutation)*

*Nitrogen Mustard*
-Hodgkin’s Disease treatment
-Extreme vesicant: Blisteringlow yield


*Nitrogen Mustard*

-Well absorbed for oral use
-Active in SLOWLY progressive malignancies

Ex.) Low grade lymphomas and CLL

*Nitrogen Mustard*
-Useful in multiple myeloma
-Used in high dose bone marrow transplant protocols
-Some activity in breast and ovarian cancer

Despite -mustine ending, it is a *Nitrogen Mustard*

-Low grade lymphoma
-Similar to Chlorambucil

*Nitrogen Mustard*
-WELL absorbed orally
-WIDEST clinical usage
-ACTIVE intermediate= Phosphoramide mustard
-Main toxicity is *myelosuppression*-Useful in breast cancers, lymphomas, and leukemias

-Helps with side effect of hemorrhagic cystitis (use MESNA) due to acrolein production

*Nitrogen Mustard*
-Useful in testicular cancer, sarcomas, and lung cancer-Toxicity of acrolein (an extremely toxic intermediary, particularly to the bladder mucosa) can be modified with MESNA (helps with side effect of hemorrhagic cystitis)

-Acrolein also produced by burning fat


*2-Mercapto Ethane Sulfonate sodium(NA)*

-Supplies free thiol group which binds to and INACTIVATES *acrolein*, the urotoxic metabolite of ifosfamide and cyclophosphamide

>mercapto: A thiol that binds strongly to mercury


*Carmustine, lomustine, semustine*

-Fat soluble

-Cross blood brain barrier

-PROLONGED myelosuppression (bone marrow suppression)

-Most common uses:
>Brain tumors

-NOT include Bendamustine (nitrogen mustard despite name)

-*Streptozocin*: Role in islet cell tumors

Alkylator Toxicity
Bone marrow suppression
-Usually occurs 7-10 days post Rx
-Recovery usually takes 7-10 days
-Occurrence and recovery more *PROLONGED with nitrosoureas*
-Stem cell can get damaged-> decreased WBCs-> InfectionsVesicant (blistering) properties
-May be severe and prolonged
-Nitrogen mustard worse than cyclophosphamide

*Hemorhagic cystitis due to ACROLEIN*
-MOST commonly seen with *cyclophosphamide and ifosfamide* BUT PREVENTED with prophylactic use of *MESNA*, forced *hydration and diuresis*, and particular attention to urinary obstruction (ex.) enlarged prostate)

Secondary malignancies
-Caused by sub-lethal DNA damage (*AML*)

Alkyl Agents (Overall)

1.) Alkyl group is REACTIVE intermediate of all alkylating agents

2.) Cell cycle NON-specific: Sometimes called radiomimetic

3.) Most are vesicants (or at least irritants) when used IV

4.) Broad range of use particularly H.D., non-hodgkin’s lymphoma, and breast cancer

5.) Myelosuppression (BM suppression) is most common dose-limiting toxicity

6. Secondary malignancies can occur particularly *AML*

*Cell Cycle SPECIFIC*
A molecule bearing a *close structural resemblance* to a molecule required for normal physiologic functioning, and exerting its effect by INTERFERING with the utilization of this essential molecule.-The use of the term in chemotherapy usually implies INHIBITION of the synthesis of DNA, RNA, or protein.

Anti-metabolites: Common properties

-*Most active during DNA synthesis= cell cycle SPECIFIC*

-INHIBIT DNA, RNA, and protein synthesis

-First family of RATIONALLY designed chemotherapy agents

-Mainly substrates for VITAL enzymes

Anti-metabolite Families

1.) Anti-folate= *Methotrexate*

2.) Pyrimidine analogues= *5-FU and ARA-C*

3.) Purine analogues= *6-MP and 5-TG*

4.) Urea analogues-> *Hydroxyurea*

Folate action in DNA synthesis
Folate action in DNA synthesis
Folate is needed with conversion of dUMP to dTMP via Thymidylate Synthase
-MTX will inhibit dUMP to dTMP
Methotrexate (Mechanism)
Methotrexate (Mechanism)

*Anti-Folate: Amethopterin*

1.) *Thymidylate synthetase* requires reduced (tetrahydro) folate to convert uridine monophosphate(UMP) to thymidine monophosphate(TMP) with dihyrofolate as byproduct.
>TMP required for DNA synthesis

2.) DHFR (dihydrofolate reductase) required to convert dihydrofolate back to tetrahydrofolate (THF)
-Main source of reduced folate for DNA synthesis

3.) *methotrexate* is similar (analog) to dihydrofolate and competes with dihyrofolate for access to DHFR

MTX (Pharmokinetics)

*Anti-Folate: Amethopterin*

-Drug active WITHOUT metabolization

-Depends on renal clearance

-Solubility properties
>MORE soluble at alkaline pH
>MTX precipitates at pH close to 5 (don’t want this to happen!)
->Should alkalinize the pH with bicarbonate (ginger ale, etc)
-Doesn’t cross BBB

Methotrexate (Resistance)

-*Often more ACTIVE if polyglutamated* >Cancer cells may not be able to polyglutamate intracellularly

-INCREASED production of DHFR via gene amplification= Drug can’t block them all

-DECREASED affinity of DHFR for MTX due to MUTATION


-Addition of glutamic acid residues INTRACELLULARLY to methotrexate

-DECREASES cellular efflux of polyglutamated drug
>Polyglutamation INCREASES effect of methotrexate by keeping drug *intracellularly*

-INCREASES drug activity

-*Cells that can’t polyglutamate are relatively resistant to effect of MTX*
>Cancer cells can be either inheritantly poor polyglutamators or acquire this trait leading to resistance

-Cancer cell mutation can DECREASE polyglutamation

Methotrexate (Clinical uses)
-Cutaneous T-cell lymphoma
-Lung cancer
-Breast cancer
-Intrathecal chemotherapy
>Give in CSF via lumbar puncture or tube to ventricles (reservoir)
Intrathecal Methotrexate

Methotrexate *does not pass BBB*

-Can be given intrathecally or intraventricularly to attain *high CNS concentrations with minimal systemic toxicity*

Methotrexate (Toxicity)
-*Bone marrow suppression*
-Skin rashes
-Hepatotoxicity: More important with chronic conditions such as Psoriasis
-Pulmonary toxicity
Methotrexate (3rd spacing)

Methotrexate collects in pleural effusions and ascitic fluid (can cause pulmonary toxicity and hepatotoxicity)

-Subsequent SLOW release of drug mimicking a slow infusion with increased bone marrow and mucosal toxicity
>Goes systemically

Leucovorin (folinic acid) Rescue

*Helpful with use of high dose methotrexate*

1.) Cancer cells in general have higher GF than non-cancer cell population

2. effect of methotrexate more rapid with higher GF cell population (i.e. cycling cells/cancer)

3. May rescue lower GF cell population (i.e. non-cancerous tissue) with EXCESS reduced folate (given after methotrexate)

4.Dangerous and timing is critical

*Leucovorin will help with preventing toxic effects of methotrexate to normal tissues*

Leucovorin Mechanism
Leucovorin Mechanism
ONLY give when using HIGH DOSE methotrexate
Other antifolate drugs
Pemetrexed (Alimta)
-multiple targets
>Lung cancerRaltitrexed (Tomudex)
>Colorectal cancer
>Breast cancer


Pyrimidines and Purines
Pyrimidines (CUT):
-Uracil (U): RNA only
>5-methyl uracil
-Thymine (T)
-Cytosine (C)Purines (GA):
-Guanine (G)
-Adenine (A)

-Nucleoside is a nucleobase linked to a pentose sugar

-Nucleotide is a nucleoside with one or more phosphate groups


*5-FU: Pyrimidine Analog*

-5-FU converted to flouro-deoxyuridine monophosphate (FdUMP)

-FdUMP competes with dUMP for *Thymidylate Synthase (TS)*

-No role for fluorine in mammalian biology

-dUMP generally uses TS + Folate to produce dTMP

-5F-dUMP will inhibit the TS so that dUMP will NOT convert to dTMP-> No thymidine produced

5-FU (Secondary mechanism)


-Acts as *false pyrimidine*

-INHIBITS transcription


*Phosphoribosyl pyrophosphate *

-*Needed to secondarily ACTIVATE 5-FU*

-*Needed to synthesize purines*

-*Inhibited by allopurinol*-> No PRPP then 5-FU has no action

-Pentosephosphate: Acts as a co-factor

-Formed from ribose 5-phosphate by ribose-phosphate diphosphokinase

-Transfers phospho-ribose groups in several reactions

Antifungal agent (5-Fluorocytosine)
-Fluorinated pyrmidine analog
-Bioactivated to 5-FdUMP-> inhibits TS in fungal cells*Similar activity of 5-FU in mammalian cells but affect fungals-> not as toxic*

5-FU (Resistances)
-INCREASED expression of TS
>Gene amplification-REDUCED drug sensitivity of enzyme (TS)

-DECREASED activation of 5-FU
>Decreased activating enzymes (mutation or under-expression) or decreased PRPP secondary to allopurinol (minor role)

5-FU (Uses)
*Colorectal Cancer*
-ENHANCED by addition of reduced folate (folinic acid).
>Folate increases the conversion of the apoenzyme to the active enzyme.
>The active enzyme incorporates flourinated pyrimidine more efficiently.
>This complex of TS, fluorinated pyrimidine, and reduced folate is called a “*ternary complex*”*Breast cancer*
-Component of first effective adjuvant therapy (CMF-> Cyclophosphamide, MTX, and 5-FU)

*Other GI malignancies*

5-FU and Folic Acid
5-FU and Folic Acid

-Folic Acid + TS + dUMP-> dTMP

-Folic acid + TS + FdUMP-> TREATMENT WORKS WITH THIS COMBINATION (prevents production of dTMP)-> Prolongs enzyme inhibition

*5-FU + Folinic acid INCREASES probability of survival*

Folinic Acid (Review)
RESCUES normal tissue from toxicity of *methotrexate (MTX)*
-Decreases toxicity by delivery of excess reduced folate bypassing MTX-INCREASES activity of 5-FU
>INCREASES toxicity/activity by enhancing inhibition of TS in presence of flourine atom

5-FU toxicity

1.) Mainly GI (*Mucositis*)

2.) Myelosupression

3.) Skin-sun sensitivity
>Venous discolaration (brownish color by veins)

“Hot coffee”

Other Pyrimidine analogs

-Capecitabine (Xeloda)

-Cytosine arabinoside (ara-C)




-abine drugs

Capecitabine (Xeloda)
Capecitabine (Xeloda)

1. Prodrug

2. Converted to 5-FU in liver then to active drug in liver and tumor tissue

3. Only used ORALLY
4. Action *mimics 5-FU infusion*

5. Toxicity is primarily *”hand/foot” syndrome*
> Secondary to gravity dependence and/or drug induced vasospasm
>More chance of an infection due to blistering-> must keep hands clean/avoid exposure

6.) Low dose given over long period of time= increased area under the curve (AUC)
>Prolonged drug exposure-> delayed toxicity

Cytarabine (ara-C)
Cytarabine (ara-C)

Arabinose sugar is substituted for deoxyribose sugar (both pentose sugars)

*Pyrimidine analog-> similar to cytosine*

Ara-C (Mechanism)

1.) Incorporated into DNA

2.) Inhibits DNA polymerase

3.) Inhibits DNA elongation

*Incorporates into DNA-> Inhibits DNA polymerase-> terminates DNA chain elongation*

ARA-C (Resistance)
>Gene amplification-*Increased activity of cytidine deaminase*: INACTIVATES the drug
>Gene amplification

-Decreased activity of deoxycytidine kinase (activates drug)

-DECREASED affinity of DNA polymerase for ARA-C

ARA-C (Uses)
*Used for AML*
-Opposite to alkylators which can cause this
ARA-C (Toxicity)

-SEVERE BM suppression

-GI mucositis

-Unusual neuro toxicity: Cerebellar dysfunction


-Cytosine analogue (H replaced by F)

-Structural similarities to ARA-C but also INHIBITS *ribonucleotide reductase (RR)*

-Anti-tumor activities against a variety of tumors (helps improve quality of life)

-Key drug in treatment of *pancreatic cancer*

-Pulmonary toxicity


*2,3 dideoxycytidine*

-*REVERSE transcriptase inhibitor*

-Also inhibits *viral DNA polymerase*


*5-azacitidine (Vidaza)*

-INHIBITS DNA methyltransferase causing *hypomethylation of DNA* leading to cell death= epigenetic effect

-Major role is in MDS (myelodysplastic syndrome).
>However, in some tumor models, hypomethylation is carcinogenic.


*Adenine and Guanine*

-a purine is a fusion of a pyrimidine ring and imidazole ring

Purine analogs
-6-mercaptopurine (6-MP)
-6-thioguanine (6-TG)
-Azathioprine (Imuran)
Purine Analog (6-MP and 6-TG)
Purine Analog (6-MP and 6-TG)

Major source of purines for formation of DNA is recycled purine derivatives (ex: Hypoxanthine)

-Enzyme required is *HGPRT* (hypoxanthine-guanine phosphoribosyl transferase)
>The enzyme PRPP synthetase is also required.

-*6-MP and 6-TG* are also excellent substrates for *HGPRT blocking* access to this enzyme by required recycled purines

-6-MP and 6-TG converted in single step to 6-thioguanosine-5-monophosphate (6-thio GMP) and 6-thioinosine-5-monophosphate (T-IMP): these are fraudulent purines and accumulation leads to “pseudofeedback inhibition” of PRPP and HGPRT

*DNA synthesis inhibited*

Note: Inosine is formed when hypoxanthine is attached to a ribose sugar

6-MP and 6-TG (Properties)

*Cell cycle specifics*

1.) Metabolized to fraudulent deoxynucleotides

2.) Incorporated into DNA inhibiting FURTHER synthesis

3.) ACTIVE during DNA synthesis

6-MP and 6-TG (Resistance)
1.) decreased affinity for the activating enzyme HGPRT (hypoxanthine-guanine phosphoribosyl transferase)
>Mutation of HGPRT2.) . Increased drug degradation
>Gene amplification via *Xanthine oxidase*

6-MP and 6-TG (Uses)
-6-MP also used for Inflammatory bowel disease (Ulcerative colitis/Crohn’s disease)
6-MP and 6-TG (Toxicity)

-INHIBITS *xanthine oxidase and PRPP*

-DECREASES circulating uric acid and xanthine: a precursor of purine synthesis

-Xanthine oxidase also required to metabolize 6-MP and 6-TG
>Leads to LONGER drug exposure

-INHIBITS de novo purine synthesis by INHIBITING PRPP

Allopurinol (Uses)

-Cytotoxic chemo causes BREAKDOWN of cells often leading to elevation in uric acid

-To prevent GOUT, allopurinol often used
>Prevents hyperuricemia

-Leads to enhanced cytotoxic effect of purine analogues: must decrease dose


Allopurinol decreases the activity of…


-INHIBITS PRPP which is needed for secondary conversion of 5-FU to 5-FdUMP

Allopurinol increases the activity of…
INCREASES activity of purine analog-increased toxicity
-INHIBITS xanthine oxidase needed to metabolize 6-MP and 6-TG to inactive metabolites-INHIBITS PRPP needed for de novo purine synthesis
>REMEMBER: PRPP is needed for purine synthesis
->Needed to activate 5-FU
->Inhibited by allopurinol

Allopurinol causes…

-Causes INCREASED purine accumulation

-Causes feedback INHIBITION of *amidophosphoribosyl transferase (Atase)*
>NEEDED to convert PRPP to phosphoribosylamine
>Rate limiting enzyme in purine synthesis

Lesch-Nyhan Syndrome
*HGPRT deficiency*
-INCREASED PRPP leads to INCREASED purine synthesis utilizing excess PRPP
-Increased uric acid

-Intellectual disability

-Self mutilating behavior

-X-linked recessive

*2-flouroadenosine with arabinose*
-Adenosine analog
-Activity in LOW GRADE lymphoma


-Adenosine analogue (2CDA)

-INHIBITS adenosine deaminase

-May be curative in Hairy Cell Leukemia


*Hydroxycarbamide: anti-metabolite*

1.) Analogue of urea

2.) Inhibits *ribonucleotide reductase* (needed to convert ribonucleotides to deoxyribonucleotides-> similar to Gemcitabine)

3.) Inhibits DNA synthesis

4.) Active in CML

5.) Resistance due to mutation or over-expression of ribonucleotide reductase

6.) toxicity: Myelosuppression, N&V, diarrhea

USEFUL in Rx of Sickle cell Disease-> Increases HbF

Summary targets of antimetabolites
Summary targets of antimetabolites
-Toxicity usually myelosupression and GI-Increased activity= increased toxicity

What are naturally occurring agents?

Active agents found in nature that INHIBIT cell replication and require minimal (if any) synthetic modification.

-Most often derived from fungi (antibiotics) or plants (plant alkaloids)


Various strains of soil fungus (streptomyces, etc)

1.) Anthracyclines (-rubicins)

2.) Anthracenedione: Can cause cardiac problems
>Mitoxantrone: Alopecia

3.) Dactinomycin

4.) Mitomycin

5.) Bleomycin



1.) INTERCALATES between base pairs BLOCKING DNA and RNA synthesis
>Insertes in backbone-> causes unwinding-> improper replication

2.) INHIBITS *topoisomerase-2 causing DNA strand breakage*
>Enzyme normally unwinds DNA to be read

3.) GENERATES *oxygen and hydroxyl free radicals* causing DNA strand breaks and cell membrane damage

Anthracyclines and naturally occurring agents: Resistances
Anthracyclines and naturally occurring agents: Resistances

*Multi-drug resistance (MDR)* mediated by membrane associated P-glycoprotein: An ATP- dependent drug EFFLUX pump

-P-glycoprotein sometimes called permeability glycoprotien

-Gene amplification

-Predominantly overexpressed in epithelium, endothelium, and BBB as opposed to lymphatic tissue

Anthracyclines (Use)
>Breast cancer (AC, FAC)
>Some role in most other tumors-*Daunorubicin*
>mainly AML (Like ARA-C)

>Mainly hematologic malignancies

>Same indications as doxorubicin

Anthracycline (Toxicity)


2. bone marrow suppression

3.) *Alopecia* (baldness)/ Hair may change texture (curly, etc)

4.) Severe nausea and vomiting

5.) Secondary malignancies

Anthracycline (Heart Toxicity)
-*CARDIAC*: Free radical generated has affinity for cardiac muscle
>Results in a dose-dependent *cardiomyopathy*>Worse with HTN or other after-load stress

>Aggravated by radiation

>Synergistic with other drugs-> Herceptin (trastuzumab)

>May be prevented or reduced with *cardioprotectant drugs* ->*Dexrazoxane (Zinecard)*
->An iron chelating agent preventing the formation of anthracycline-generated free radicals


Actinomycin D

Mechanism of action:
-Binds at transcription initiation complex INHIBITING RNA elongation by RNA polymerase

Activity: Mainly pediatric tumors especially *Wilm’s tumor*

Toxicity: myelosuppression and severe vesicant (blistering)


Mechanism of action:
-Acts somewhat like an *alkylator* causing potent CROSS LINKING
-May have preferential activity in HYPOXIC conditionsMechanism of resistance:
-MDR (p-glycoprotein mediated)

-Main current use is in Rx of anal cancer along with 5-FU and radiation to help spare anal function
-May also be used for intra-vesical Rx of superficial bladder cancer (unlike cyclophosphamide/ifosfamide)

-Associated with *TTP (thrombotic thrombocytopenic purpura)*
>Kidney failure

-Often fatal


*G2 Drug*
Mechanism of action:
-Produces *single strand and double strand breaks*
-ONLY drug with *predominantly activity in G2 disrupting synthesis of components needed for mitosis*Mechanism of resistance:
-MDR (p-glycoprotein mediated)

-Testicular cancer
-Hodgkin’s disease (ABVD)
-MINOR activity in a number of other tumors
-Useful as pleurodesing agent

-Free radical produced directly *toxic to lung*; can cause pulmonary fibrosis (Lance Armstrong refused)
-MUST monitor PFT’s
-May cause acute anaphylactic reaction: Test dose often given
-Skin toxicity

Bleomycin side effect (x-ray)
Bleomycin side effect (x-ray)
-Lung Fibrosis
Plant alkaloids
*Vinca alkaloids* derived from periwinkle plant (-ine)
-Vinorelbine*Taxanes* are alkaloid esters derived from Yew tree (-TAXEL/-AXANE)

*Podophyllotoxin* derived from the Mandrake plant (Harry Potter!!!) (-POSIDE)

4. *Quinoline alkaloids* from the Camptotheca acuminata (Happy Tree) -TECAN

Splindle inhibitors
Splindle inhibitors
Vinca Alkaloids
-Vinblastine , Vincristine , Vindesine , VinorelbineTAXANES
-Paclitaxel (Taxol)
-Docetaxel (Taxotere)


Vinca Alkaloids (Mechanism)

-Bind to microtubular protein (tubulin)

-Cause DEpolymerization of microtubules

-PREVENTS spindle formation-> Leads to *mitotic arrest*

RESISTANCE: MDR (p-glycoprotein mediated)

Vinca Alkaloids (Toxicity)


-Tubulin has similarities to *myelin*
>As a consequence *peripheral neuropathy* occurs

>Sensory neuropathy (reversible)

>Motor neuropathy (irreversible)
->Much more serious condition

Ex.) Can’t walk well with morning, vision problems, etc


Vinca alkaloids (Therapeutic uses)
-Hodgkin’s disease
-Lung cancer
-Breast cancer
*Paclitaxel*: Derived from bark of Pacific Yew
-Kills tree*Docetaxel*: From needles of Pacific Yew
-Tree survives

Abraxane-nab paclitaxel
-Nano particle albumin bound
-Less toxicity

Cabazitaxel: PARTIALLY synthesized

Taxanes (Mechanism of action)

-Binds to tubulin

-ENHANCES tubulin polymerization (opposite of Vinca Alkoids)

-PREVENTS *spindle disassociation* causing mitotic arrest

-Resistance: MDR but NOT for *Cabazitaxel*

Taxanes (Use)

-Original indication for ovarian cancer (paclitaxel)

-VERY active in breast cancer

-ACTIVE in lung cancer

Taxane (toxicity)

-Bone marrow


-Myalgias and arthralgias

-Neurologic (Neuropathy)
>Sensory (reversible): CN VIII, etc
>Motor (irreversible)

-Skin: Particularly nails (*Multiple Beau’s Lines*)

-Use of STEROIDS to prevent acute toxicity is critical


Taxanes on nails
Taxanes on nails
*Beau’s Lines*
-Affects the growth plate
-Multiple white lines seen on nails
-One line represents a cycle of chemotherapy

Extract of Mandrake plant: nightshade family

-Used as folk remedy by American natives for emetic, cathartic, and antihelmintic

-Mentioned in Harry Potter and Bible

*Inhibits Topoisomerase II*

Podophyllotoxins (Mechanism)

-INHIBITS *DNA topoisomerase-2* and tubulin polymerization

-Topoisomerase enzymes allow breakage of both DNA strands, unwinding of DNA, and reannealing of the strands

-INHIBITS DNA and RNA synthesis


Podophyllotoxins (Uses)
-Testicular cancer
-Lung cancer (especially small cell)
-Minor activity in a variety of cancers*Unusual toxicity: UNPREDICTABLE HYPOTENSION*

*Quinoline alkaloids* from the Camptotheca acuminata (Happy Tree derived from China generally used as a purgative) –

*Inhibit Topoisomerase 1*

Camptothecins (Mechanism)

-*INHIBITS topoisomerase 1*

-Leads to ARREST of DNA replication and ultimately cell death



-Primarily used in metastatic colon cancer

-Causes EXCESSIVE diarrhea requiring use of anti-motility agents

-Also has unique acute cholinergic side effect requiring use of *atropine*
>Sudden salivation,tearing, urge to defecate, bradycardia


-Primarily used in SMALL cell lung cancer and ovarian cancer

-Main toxicity is *myelosuppression*

Camptothecins (Resistance)

-NOT MDR mediated

-Change in Topoisomerase 1 structure (mutations)

-Mechanism causing DECREASED accumulation

Major Toxicities of naturally occurring products


-Anthracyclines= Cardiac

-Anthracenediones= Cardiac

-Dactinomycin = Myelosuppression

-Mitomycin = TTP

-Bleomycin= Pulmonary

Plant alkaloids

-Vinca= Neurologic

-Taxanes= Neurologic

-Podophyllotoxins= Myelosuppression

-Camptothecins= Gastrointestinal

Naturally occurring antibiotics (summary)

-Work better in cycling cells but not strictly cell cell cycle specific (intercalation) *except Bleomycin= G2*

-Specific toxicities mainly related to free radical intermediate

Naturally occurring plant alkaloids (summary)

-Vincas and taxanes cell cycle specific (mitosis), *neurotoxic*, and broad range of activity

-Podophyllotoxins inhibit topoisomerase-2 activity, cell cycle specific

-Camptothecins have topoisomerase-*1* activity, EXTREME GI toxicity (cholinergic side effect)

Miscellaneous agents

-Agents not falling exactly into one of the other major families of chemotherapy.

-All have some but not all properties of one of the major families.

General properties of heavy metals (miscellaneous agents)
*Cisplatinum, Carboplatinum
and Oxaliplatinum*1.) Heavy metals
2.) Can mold into shapes
3.) Act as alkylators
4.) Common toxicity is *neurologic* (stays forever in body)

5.) Other toxicities:
-Nephrotoxicity: cisplatinum

-Myelosuppression: Carboplatinum

-Cold intolerance: Oxaliplatinum

Cisplatin (Platinol) and Carboplatin (Paraplatin)
Cisplatin (Platinol) and Carboplatin (Paraplatin)
*Platinum Complex*
-Inserts in locations other drugs cannot
-TOXIC effects
Platinum Resistance

-Increased cellular efflux (*MDR*)

-Increased production of intracellular thiol (Glutathione)

-Increased DNA repair enzymes

*Platinum profoundly most active as FIRST line drug!*

Platinum (Mechanism)

-Causes necrosis or apoptosis of cells of proximal tubule (PCT) leading to *wasting of magnesium and potassium*

-Without injury Magnesium and Potassium usually handled by distal tubule


-Curative for most *germ cell tumors*

-significant activity:
>Lung cancer
>Ovarian cancer
>Unknown primary

Side effect: Nephrotoxicity


-Same spectrum of activity as cisplatinum but *LESS nephrotoxicity and MORE myelosuppression*

-Used in breast cancer, ovarian cancer, and lung cancer



Unique activity in colon cancer

*Side effect: cold intolerance*

Platinum Toxicity: Prevention of Nephrotoxicity

-INCREASE both parenteral and oral hydration

-Use volume expanders such as Mannitol to force diuresis

-REPLACE both potassium and magnesium

-*USE of Amifostine*
>Thiophosphate *cytoprotective agent* SCAVENGES reactive cisplatin metabolites in normal tissue

Platinum Toxicity: Prevention of Neurotoxicity

-some protective effect of calcium and magnesium INFUSIONS (recently refuted)

-Cold induced neuropathy can be prevented by AVOIDANXCE of cold air and drink


*Naturally occurring enzyme*

-Guinea pig serum

-Mechanism of action: tumor cells, particularly malignant lymphocytes (as opposed to normal cells) have relatively low levels of asparagine synthetase and L-aspaginase hydrolyses circulating asparagine
>This leads to LESS availability of asparagine for tumor cells thereby *INHIBITING tumor protein synthesis and cell proliferation.*

-Non-malignant cells are relatively protected

*Activity mainly for pediatric ALL*

Arsenic Trioxide
-Derived from arsenic and a “metalloid”
-Combined with *all-trans retinoic acid for treatment of acute promyelocytic leukemia (APL)*-Historically used in traditional Chinese medicine

-Mechanism of action uncertain-> Induces apoptosis

-Toxicity: interrupts ATP production leading to multi system failure

All-Trans Retenoic Acid
All-Trans Retenoic Acid

-Classified as a retinoid

-Promotes cell differentiation leading to APOPTOSIS

-Indication: APL

Toxicity: headache, fever, dry skin, flu like symptoms, and infections


*From BORON (metalloid)*

*Proteosome Inhibitor*

-Cytoplasmic protease complex required to degrade unneeded proteins-> Inhibited by * bortezomib (Velcade)*

-Multiple myeloma (MM)

-Mantle cell lymphoma (MCL)


*Derived from Glutamic Acid*

-Sedative introduced in the 1950’s
-Horrendous birth defects
-Found later to inhibit angiogenesis by interrupting processes mediated by *VEGF*

-Reintroduced along with its analogue, lenalidomide, for Rx of *multiple myeloma*

Lenalidomide: Mechanism of action

Took over Thalidomide

1. Anti-angiogenesis (Inhibit VEGF)
>Extends life

2. decreases BM stromal cell support

3. anti-Osteoclastic

4. immunomodulatory activity


Multiple Myeloma

Miscellaneous agents (Summary)
-Alkylating function, CCNS
-Severe nephro and neurotoxicities; cold intoleranceL-asparaginase
-INHIBITS protein synthesis

-Arsenic trioxide / All trans retinoic acid
>INDUCES apoptosis in certain leukemia (APL)

-INHIBITS proteosome (Velcade)

Thalidomide/Lenalidomide: Inhibits angiogenesis

Families of chemotherapy
Alkylating agents
-Nitrogen mustard derived
>BendamustineNitrosureas (-mustines)

Other alkylators

Antimetabolites (culprit for mucositis)

Naturally occurring compounds

-Fungal derived (antibiotic)

-Plant derived
>Vinca alkaloids

Miscellaneous agents
-Platinum derived
-Arsenic troxide
-All trans retinoic acid

Sites of action of Chemotherapeutic agents (Diagram)
Sites of action of Chemotherapeutic agents (Diagram)
Targeted Therapy
A type of medication that blocks the growth of cancer cells by interfering with *specific targeted molecules needed for carcinogenesis and growth*: Often overexpressed or mutated in cancer cells
-RATHER than by simply interfering with rapidly dividing cells such as using chemotherapy-Theoretically more specific and less toxic than traditional chemotherapy

-The target is often measurable >Ex: HER-2/neu

Cancer Promotion (Examples)
Cancer Promotion (Examples)

-GFs: VEGF, EGF, Estrogen


-GF re ceptors: ras, EGFR, eRBb2


-Autocrine promotion

-Angiogenic factors

Classes of targeted therapy
-Anti-hormonal therapy
>Including corticosteroids-Monoclonal antibodies

-Signal transduction inhibitors

-Linker therapy

Anti-hormonal therapy
-Primarily useful in Rx of breast cancer
>Estrogen receptor is more sensitive post-menopausal due to less circulating estrogen*Anti-androgens*
-Primarily useful in Rx of prostate cancer



-Took over oopherectomy (removal of fallopian tubes and ovaries)

-Blocked estrogen receptor in breast *not endometrium*

-Effective in treatment of breast cancer but serious side effects

-More effective on post-menopausal women
>Use for pre and post menopausal women

Tamoxifen (Mechanism of action)

*Selective estrogen-receptor modulator= SERM*

-A WEAK estrogen that works by BLOCKING estrogen receptor (ER) in breast cancer cells

-Acts like ANTI-estrogen in breast

Delivery: Taken orally daily

Prevent G1

Tamoxifen (Toxicity)

-Thromboembolic disease (clots): Estrogen effect

-*Endometrial cancer*: Estrogen effect

-HOT FLUSHES due to anti-estrogen effect


Tamoxifen (Analogs)
-*Raloxifene*: SERM that helps treat osteoporosis
>Not first line for breast cancer, despite blocking ER for breast cancer and NOT causing endometrial cancer.-Faslodex: IRREVERSIBLE blockade of ER

*Thromboemoblism can still occur due to estrogen effect*

Resistance to Tamoxifen

ER= Estrogen Receptor

-Change in expression of ER: At the gene level

-Mutation of ER: Cannot bind as efficiently

-Selection of ER NEGATIVE cells: survival advantage

Roloxifen vs. Tamoxifen
*Roloxifen* acts similarly to Tamoxifen (but with less endometrial cancer) but clinical trials were exclusively for *osteoporosis* and cancer prevention NOT treatment for breast cancer
>NO indication for breast cancer treatment-BOTH drugs: Anti-hormonal agent INHIBIT cell cycling (G1) allowing cells to go thru apoptosis

Aromatase Inhibitors

*Aromatase inhibitor: INHIBIT transformation of androstenedione to estrone and testosterone to estradiol*

-Used for metastatic breast cancer

-ONLY for post-menopausal women
>If used premenopausally-> INCREASED LH & FSH-> HYPERSTIMULATION of ovary-> can be used to INDUCE ovulation

*Aminoglutethimide; Anastrozole, Letrozole, Exemestane (ALE)*

*Aromatase inhibitor*
-COMPLETELY block estrogen synthesis
-Requires concurrent steroid
-NO longer used
Third generation Aromatase Inhibitors
*Aminoglutethimide; Anastrozole, Letrozole, Exemestane*Toxicity due to *estrogen withdrawal*

-Osteoporosis: Can give vitamin D to help



-Walking can help alleviate symptoms

*Post menopausal women only*

Aromatase Inhibitors: Premenopause

-DECREASES estrogen production by ovary

-INCREASES LH , FSH release by pituitary

-INCREASES attempt at estrogen production by ovary= *hyperstimulation*

-Leads to development of CYSTIC ovaries and ultimately does NOT STOP ovarian estrogen production

*DUE to hyperstimulation-> can be used to INDUCE ovulation*

Tamoxifen vs. Aromatase Inhibitors (Mechanism diagram)
Tamoxifen vs. Aromatase Inhibitors (Mechanism diagram)
Tamoxifen: BLOCKS the estrogen receptor and can be used in both the pre- and post- menopausal settings.
-Antiestrogen effect on the breast but estrogen effect on the uterus (endometrial cancer as a side effect)Aromatase Inhibitors (Aminoglutethimide; Anastrozole, Letrozole, Exemestane): EXCLUSIVELY used for POST-menopausal setting when the adrenal gland is the major source of estrogen precursors


DECREASES activity of estrogen receptor= *Down regulation*

-*Megestrol acetate*


Side effects: Hirsutism, acne, abnormal lipid (LDL rises= weight gain), hyperventilation, and elevated glucose levels

LHRH/GnRH Analogs

DECREASES pituitary release of LH and FSH resulting in DECREASED estrogen synthesis by ovary





-Decrease pituitary release of both LH and FSH due to down regulation
>Flare effect first 10 days: Use GnRH antagonist (Ganirelix, Cetrorelix, Abraelix to prevent)

*Breast and prostate cancer*

Androgen Receptor Blockers
-Flutamide (Euflex)
-Bicalutamide (Casodex)
-Enzalutamide (Xtandi)Delivery: Oral and daily

-Hot Flushes
-Andropause (Drop in testosterone)

*Resistance similar to tamoxifen*

Pituitary Inhibition
*GnRH/LHRH analogs*
Leuprolide, Nafarelin, and GoserilinMechanism of action: Paradoxically DECREASE pituitary release of both LH and FSH (after INITIAL INCREASE) due to receptor down regulation

-Results in DECREASED estrogen and testosterone production

-Active in both prostate cancer and breast cancer
>More commonly used in PROSTATE cancer

-Toxicity: Transient “flare” effect (lasts approximately 10 days)



-Must use with steroids

-DECREASES both *androgen and corticosteroid production* by INHIBITING *17- alpha hydroxylase*

Abiraterone (Mechanism)
Abiraterone (Mechanism)

*17 Alpha hydroxylase inhibitor*

ADT (Androgen deprivation therapy) such as treatment with LHRH therapy or orchiectomy (removal of testicles), suppresses testicular androgen production but DO NOT affect androgen production by the adrenals or in prostatic tumor tissue

*Abiraterone acetate* INHIBITS the *CYP17 enzyme complex* that is required for testosterone biosynthesis in testes, adrenal, and prostatic tumor tissue
>NO DHEA and androstenedione which are androgens and the precursors of testosterone

-Does not suppress hypothalamus/pituitary/gonadal stimulation= ACTH rises!
>Mineralcorticoids are continuously produced-> High Salt/Fluid retention= cause hypokalemia and HTN

Abiraterone must be used with ________ to prevent ACTH production?
*Concurrent corticosteroids to prevent ACTH production*
Corticosteroids (Mechanism of action)


-Malignant lymphocytes have steroid receptor that when activated can result in LYSIS of lymphocytes possibly by *inducing APOPTOSIS*

Corticosteroids (Activity)

*Primarily Hodgkins and NHL*

-Major role in *supportive care*


-Appetite stimulant

-DECREASES cerebral edema


Corticosteroids (Toxicity)

-Fluid retention-> Aldosterone

-Glucose intolerance-> Cortisol

-Proximal myopathy/neuropathy


-Immunosuppression: Anti-inflammatory

-INCREASED appetite

-Skin changes

-STRESS ulcers

What drugs cause proximal myopathy/neuropathy?


-Vinca Alkaloids




Monoclonal Antibodies (Types)
Monoclonal Antibodies (Types)

Drugs end with *mab*

Murine MAb: MOMAB
-Culprit for *hypersensitivity*
>High levels of NEUTRALIZING antibodies

Chimeric MAb: XIMAB
>LOW levels of neutralizing antibodies

Humanized MAb: ZUMAB
>LOW levels of neutralizing

Human MAb: MUMAB
>LOWEST/NO levels of neutralizing antibodies

Monoclonal antibodies Types
-Make cancer cells more visible to the immune system
>Nivolumab-BLOCK growth signals

-STOP new BVs from forming

Lymphocyte and bone Receptors


PD-1= Nivolumab

EGFR= Cetuximab

VEGF= Bevacizumab

HER2= Trastuzumab/Pertuzumab

RANK ligand= Denosumab

AKA Rituxan
*Make cancer cells more visible to the immune system-> CD20*Target is CD20 found on *B- cell lymphomas*

-CD20: Mediates antibody DEPENDENT cellular toxicity and complement dependent cytotoxicity by making *lymphocyte more visible*
>Making it more visible to NK cells



*Make cancer cells more visible to the immune system-> PD-1 (Checkpoint INHIBITOR)*

INCREASES immune response

-PD= Programmed cell death
>Expressed on T-cells and B-cells
>Binds 2 ligands= PD-L1 and PD-L2-> Down regulates the immune system-> Promotes SELF tolerance

HUMAN (fully)



*-BLOCK growth signals-> target EGFR*

-Used for Squamous cell head and neck cancer; wild type k-ras colon cancer

-Can cause SKIN RASH: indicate the appropriate target has been inhibited-> Acneiform eruption
>Low doses of steroid creams and antibiotics needed




*Stop new blood vessels from forming-> Target VEGF*
-Antiangiogenic drug helps to prevent BV development-> tumors will diminish in size

USED FOR mainly *colon cancer and refractory gliomas*

Toxicity: Wound healing




*Binds to CTLA-4-> Blocks INHIBITORY signal*

Used for *metastatic melanoma* (immune sensitive cancers-> DTIC and Vumrafenib used for MM too)
CTLA= Cytotoxic T-lymphocyte-associated antigen-4
>An inhibitory regulator of T-cell immune response
>INHIBITS immune defense against tumor cells
>Ipilimumab will block CTLA-4 = *disinhibiting T-cell activity*

HUMAN (Fully)

Trastuzumab (Herceptin)/ Pertuzumab (Perjeta)

*Her-2/neu over expression in breast cancer*

-Up to 30% of breast cancer OVEREXPRESS HER2 gene

-INCREASES both response rate and survival in metastatic breast cancer

-INCREASES “cure” in early stage HER positive breast cancer

-HER2 may also be over expressed in gastric cancer

-First monoclonal Ab associated with improved survival/cure when used adjuvantly in Rx of *epithelial malignancies*

-Toxicity= cardiac (DONT use with Doxrubicin/Anthracyclines)
>REVERSIBLE cardiac toxicity



*Binds to RANKL-> Inhibits osteoclastic activity*

-MANY cancers go to bone-> stimulate *osteoclast activity*
-> Osteoclast makes Receptor Activator of Nuclear Factor kappa (RANK)

-*Denosumab* DECREASES bony complications-> improves bone density

-Used for postmenopausal women at risk of fracture

-Side effects: Hypocalcemia, rash, eczema, dermatitis, INCREASED risk of osteonecrosis in jaw


Signal transduction inhibitors

Protein Kinase inhibitors: Critical components of signal transduction pathways influencing gene transcription and/or DNA synthesis


-Tyrosine kinase (TKIs): *End in ib*

-mTOR: serine/threonine protein kinase

-B-RAF: Member of Raf kinase family

-MAPK: Mitogen activated protein kinase


*Tyrosine Kinase Inhibitors*

-May be associated with a TRANS membrane cell surface receptor

-May have NO associated cell surface receptor identified

-Prevent phosphorylation

End in *ib*


TKIs (Examples)

-EGFR HER2 domain (ErbB-2): Lapatinib

-EGFR NON-Her-2 domain: Gefitinib and Erlotinib

-VEGFR: Sunitinib and Sorafinib



EGFR Receptor: HER2 domain (ErbB-2)


-Trastuzumab directly binds to HER2, while Lapatinib will block the HER2 domain
(Both for breast cancer)



EGFR NON-Her-2 domain





Renal Cell Carcinoma





VEGF vs VEGFR blockers
VEGF vs VEGFR blockers

VEGF Blockers= Bevacizumab/Avastin (colon cancer)

VEGFR Blockers:
-Sunitinib (RCC)
-Sorafinib (Hepatoma)
>Both took over IFN but not much much more efficacy

Non cell surface receptor associated TKIs
-Target: Product of mutated oncogene (*Bcr-Abl oncogene*)*CML and GI stromal tumors*

*Nilotinib has similar action*

Imatinib (mechanism)
Imatinib (mechanism)
INHIBITS the *tyrosine kinase activity* of the protein product of the *Bcr-Abl oncogene* that is commonly expressed in CML
Imatinib (Therapeutic use)
-Chronic Myelogenic Leukemia (CML)
>Bcr-Abl gene-GI stromal tumors (expressing the *c-kit tyrosine kinase*)
>Interstitial cell of CAJAL


*Resistance: Mutation of the Bcr-Abl gene*

Imatinib (Toxicity)



-Fluid Retention

B-Raf Inhibitors


-INHIBITS mutated *B-raf protein kinase*


-Uses: *metastatic melanoma* (so is Ipilimumab and Dacarbazine (DTIC))

Efficacy of vemurafenib in metastatic melanoma
More effective than DTIC (Dacarbazine)
Vemurafenib (Toxicity)
Vemurafenib (Toxicity)
-Rash (sometimes)
-Unusual cutaneous squamous cell carcinoma (SCC)
m-TOR inhibitors
-Causes immunosupression
-Used to prevent transplant rejection*Sirolimus/Rapamycin; Temsirolimus; Everolimus*



INHIBIT tumor growth

UNKNOWN mechanism

May reverse resistance to anti-hormonal agents (Bolero trial)

-Many analogs made due to this: Temsirolimus; Everolimus

Temsirolimus and Everolimus


Used for Renal Cell Carcinoma (RCC)

-Activa against M-TOR

Nomenclature hints

Monoclonal antibodies= -ab

TKIs: -ib

mTOR inhibitors: -olimus

Chemo vs targeted therapy
-Target is known
Ex.) TS (Thymidylate Synthase) and DHFR (MTX)-Usually not measurable

-Overexpression/ mutation leads to RESISTANCE

-Targets ALL cells




Targeted Therapy
-Target known
Ex.) EGFR (Cetuximab), CD-20 (Rituximab), etc
-Usually measurable
-Overexpression/mutation often exploitable
-Often only targets cancerous cells

-Toxicity unpredictable



Human response to viral infection is to synthesize endogenous glycoproteins that “interfere” with viral replication

-Activity demonstrated in melanoma, renal cell carcinoma, hairy cell leukemia (cladribine can be used), T-cell lymphoma, and early stage CML

-Toxicity= Predictable >Extreme flu-like symptoms, myelosuppression, and hepatotoxicity

-Major role in cancer RX: adjuvant Rx of high risk melanoma

*Hairy cell leukemia and CML*

IL-2: Cytokine immune system signaling molecule
-Bind to IL-2 receptors on T-lymphocytes
-IL-2/IL-2R interaction stimulates growth, differentiation, and survival for cytotoxic T cellsNOT really used today due to SHOCKING LUNG

*Tumor necrosis Factor*
Can cause apoptosis
-Not really used in therapy
HPV vaccine


-HPV 6 and 11 cause condyloma accuminata

-HPV 16 and 18 cause CERVICAL cancer

Resistance to chemotherapy
1.) INCREASED expression of target proteins
Ex.) MTX resistance associated with overexpression of DHFR due to gene AMPLIFICATION2.) INCREASED DNA repair
Ex.) Important in RESISTANCE to alkylators and cisplatinum due to gene AMPLIFICATION

3.) Failure of drugs to enter a cell or increased efflux from cell regulated by multidrug resistance gene (*MDR also called p-glycoprotein*)
Ex.) Most naturally occurring agents (gene amplification) -> exceptions are *Camptothecins and Cabazitaxel*

4.) Inability of drug to PENETRATE tumor
Ex.) LARGE hypoxic tumors such as sarcomas
brain tumors (blood brain barrier)

5.) Target protein no longer available
Ex.) ER in breast cancer

6.) Target molecule altered
Ex.) VEGFR or VEGF mechanism-> gene mutation

7.) Formation of trapping agent
Ex.) *Glutathione mechanism*: Reacts with agents such as antibiotics and platinum
-Probably gene amplification

8.) DECREASED activation of prodrug or increased metabolism of active drug
Ex.) Antimetabolites such as 6-MP, 6-TG, ARA-C, 5-FU
>Mechanism: DECREASED activity of tumor cell enzyme that converts prodrug to active drug or increased inactivating enzyme
>Gene mutation and gene amplification

Strategies to prevent resistance
1.) Combination chemotherapy
-Different mechanisms of resistance
-Different mechanisms of action
-Different toxicities
Ex.) ABVD, BEP, FAC-TH2. dose intensity
-Exposure of tumor to exceedingly high doses of an agent BEFORE resistance can occur
-Seldom has this been successfully employed in epithelial tumors
-Main role is in *leukemias and lymphomas*

3. *Agents to REVERSE resistance*
-Cellular efflux may be INHIBITED by calcium channel blockers
-No clinical role yet
-mTOR inhibitors to reverse anti-hormonal resistance (Bolero trial)
-Folinic acid (Leucovorin) for 5FU

Adjuvant Chemotherapy

-Chemo given IN ADDITION to primary therapy to increase cure rates

-Strategy employed in Rx of early stage breast cancer, colon cancer, osteogenic sarcoma

-Practical application of Gompertzian growth principles

Induction Chemotherapy

-ATTEMPT to “induce” complete RESPONSE in chemo-sensitive tumors

-Strategy employed in Rx of most acute leukemias

-No other primary therapy available

Consolidation and maintenance chemotherapy

-Attempt to “consolidate” an induced response with further HIGH dose chemo and “maintain” a response with further low dose chemo

-Strategy most often employed in *acute leukemia*

Neoadjuvant chemotherapy

-Chemotherapy given PRIOR TO primary therapy to achieve cyto-reduction to help better facilitate more effective primary therapy such as surgery

-Strategy often employed in locally advanced breast and rectal cancer

Palliative chemotherapy

-Chemotherapy given with primary goal of *improving quality of life* and secondary goal of extending life

-Strategy used in essentially every type of cancer

Chemo is initially given after removal of the primary tumor when there is no evidence of residual disease. This type of chemotherapy is called:
1. induction chemo
2. consolidation chemo
3. adjuvant chemo
4. palliative chemo
5. targeted chemo—-

Primary treatment was removal of tumor, so then the chemo is happening AFTER= Adjuvant

Toxicity of Chemotherapy (Acute)
-Alopecia: Baldness
-Nausea and vomiting
-Skin changes
ACUTE toxicity of chemo
-Predictable-Most commonly seen with *anthracyclines, taxanes, and some alkylating agents*

-Occurs 3 weeks after first cycle

-Hair continues to grow but is BRITTLE
>Frail, fragile, can fall off

-When hair regrows often different texture

Alopecia (Prevention)

-Cold cap: INEFFECTIVE and may decrease efficacy

-Avoid concurrent toxins

-Certain drugs like *mitotoxantrone*

Nausea and vomiting

ACUTE toxicity of chemo

1.) Worse in YOUNG than elderly

2.) Most commonly seen with platinum, anthracyclines, IV nitrogen mustard derived alkylators

3.) Large psychological component (anticipatory vomiting)

5.) Used to be main cause of prematurely discontinuing chemo

Nausea and vomiting (Prevention)

-Light meals

-Amnesics: Mild tranquilizers

-Multiple drugs

Nausea and Vomiting (Active Drugs)
1.) 5HT-3 Antagonist: *Ondansetron*
>Chemo induced nausea and postoperative nausea-> can cause constipation2.) Anti-histaminics: *Prochlorperazine*

3.) Anti-dopamines:
>Dopamine normally inhibits ACh-> more ACh-> increased LES tone and enhances gastric emptying (also for GERD); can cause parkinsonism and hyperprolactinemia

4.) Minor tranquilizers: *Lorazepam*

5.) Steroids *Dexamethasone*

6.) THC

7.) *Aprepitant (Emend)*: Blocks neurokinin 1(NK1) receptor
>Substance P antagonist that blocks NK1 receptor


*Acute Toxicity form chemo*

1.) Most important side effect
2.) Biggest cause of Rx related deaths

3.)Predictable to a degree:
-White count DECREASES by 7-10 days

-Platelets a bit later

-RBCs decrease by approximately 1 % per day

4.) often associated with *severe mucositis creating a “perfect storm” for infection*

Myelosuppression (Treatment)

1.) Avoid crowds

2.) Washing

3.) Report fever or chills immediately

4.) If low absolute neutrophil count with fever = immediately treat with broad spectrum antibiotics

5.) If fever persists= consider fungal infection

6.) For subsequent cycles consider dose reduction, CSF support, or both

CSF Support

*Colony stimulating factors*

1.) Granulocyte colony stimulating factor (or GM CSF )
-Has to be used prophylactically
-Decreases infection related hospitalization and death
-Causes *bone pain*

2.) Erythropoietin
-INCREASES RBC mass (for anemia)
-DECREASES blood transfusion requirement
-Very important if transfusion unacceptable

Prevention of myelosupression
Use proper drugs
Ex.) Vincristine-> prevents Hodgkin’s, NHL, etc

Acute toxicity due to chemo

1.) Most commonly seen with antimetabolites

2.) Usually occurs at time of lowest blood counts

3.) Often painful leading to dysphagia and diarrhea-> results in electrolyte disturbance and malnutrition

4.) Often associated with yeast infection

5.) Major cause of sepsis (neutropenic patients)

Mucositis (Treatment)

1.) Intensive mouth care

2.) Pre- dental assessment: Check for cavities, sharp edges, etc.

3.) Maintain good hydration
-Rehydration solutions often required

4.) Mouth wash containing local anesthetic, bicarbonate, antifungal and occasionally anti-histamine required

5.) Dose adjustment

6.) Occasionally feeding tube required

7.) Barrier preparation available

Skin Changes
Skin Changes

Acute toxicity due to chemo

1.) Extravasation is biggest concern particularly with IV alkylators, naturally occurring products
>Fluid gets outside tissue and accumulates

2.) Antimetabolites can cause *discoloration* but are NOT vesicants
>Particularly along the vein

3.) Many agents associated with nail changes particularly taxanes (Beau’s Lines)

4.) Disabling “hand-foot” syndrome commonly occurs with infusional chemo and *capecitabine*

5.) *Acneiform rashes* (CETUXIMAB)
-Common with many targeted therapies particularly EGFR inhibitors and steroids
-May be marker of response

Skin changes: Extravasation

Extravasation of alkylating agents or naturally occurring products should be considered an emergency. Immediate action required as follows:

1.) DISCONTINUE infusion

2.) Ice and elevate limb

3.) Liberally use anti-inflammatory agents and anti-histamines

4.) Frequent observation to assess for extension of reaction

5.) Consult plastic surgery

IV LEAK-> caution as amputation can occur

Hand Foot Syndrome
Hand Foot Syndrome

“hand-foot” syndrome

-Dose reduction
-Skin emollients

*Capecitabine side effect*

Acneiform Rashes
Acneiform Rashes

-Correlate with activity of EGFR inhibitors

-Topical antibiotics and steroids


Oxaliplatin (Toxin)

*Acute toxicity of chemo*

Oxaliplatin induced pharyngolaryngeal dysesthesia
-Usually transient
-Aggravated by cold air or fluids

*AVOID COLD as intolerant to it*

Irinotecan (Toxin)
*Acute toxicity of chemo*
INDUCED acute cholinergic syndrome-Hypersalivation, acute diarrhea, bradycardia, etc

*Treat with ATROPINE*

Tumor Lysis Syndrome

*Due to cells lysis*

-Increase potassium

-Decreased calcium

-Increased uric acid

-Medical emergency

*Need IV, electrolytes, and ALLOPURINOL*

Pancreatitis (Drugs)

*Acute toxicity of chemo*

-L-asparaginase (protein synthesis inhib)
-Azathioprine (Inhib DNA methyltransferase)
-6-MP (purine analog blocking HGPRT)
-Ara-C (Inhibits DNA polymerase)

-Other anti-metabolites




Sub-acute toxicity
1.) Neurologic Toxicity
2.) cardiac toxicity
3.) nephrotoxicity
4.) pulmonary toxicity
5.) hematologic toxicity
6.) vasculopathy
Neurological Toxicity

*MOST COMMONLY SEEN WITH: *vinca alkaloids, taxanes, and platinum*

Nature of disability
-Sensory: Most common
-Usually reversible (except platinum)

-Motor: occurs late

-Autonomic= Unpredictable
>Usually GI=Constipation

Cardiac Toxicity
Cardiac Toxicity

*Anthracyclines, 5-FU, and high dose cyclophosphamide*

>Dose dependent cardiomyopathy>Free-radical mediated
>Require frequent monitoring of cardiac function
>Worse with hypertension or radiation
>May be prevented with cardioprotective agent-> *Dexrazoxane (Zinecard)*; avoid using with Herceptin (trastuzumab)

>Unpredictable coronary SPASM
>Also seen with capecitabine

-High dose cyclophosphamide
>Direct cardiac toxin

>Appears to be due to anti-HER2 effect on heart

Prevent Cardiac Toxicity
1.) Careful monitoring of dose
>Anthracycline toxicity is dependent on cumulative dose2.) Baseline and follow-up cardiac ejection fraction monitoring
>If greater than 10% drop from baseline-> may have to DISCONTINUE drug

3.) Avoid concurrent cardiac toxins
Ex.) Trastuzumab, radiation, etc.

4. Use of cardioprotective agent (Dexrazoxane (Zinecard))

Most commonly seen with:
-Cyclophosphamide/Ifosfamide (Nitrogen mustards)
Nephrotoxicity (Mechanism)
1.) Cisplatinum
-dose dependent
-Proximal tubular toxin
-Can partially prevent with hydration and *amifostine*
-Need to monitor for potassium and magnesium wasting2.) Mitomycin-c
-Can cause TTP with renal failure
-Probably free radical mediated
-Often irreversible

3.) Cyclophosphamide and ifosfamide
-Acrolein mediated hemorhagic cystitis
-May be prevented with *MESNA*

Pulmonary Toxicity

*Bleomycin and Gemcitabine*

Bleomycin mechanism:
-A free radical intermediate that interacts with heme asociated iron in pulmonary interstitium
-Toxicity can be acute or cumulative
-Patients must be followed with serial pulmonary function tests monitoring for diffusion defects
-Lance Almstrong avoided!

Delayed hematologic Toxicity
Most commonly seen with:
-All alkylators and Mitomycin
-AnthracyclinesWill have:

-Sub lethal DNA damage
-TTP idiopathic , mitomycin-related

Anti-angiogenesis drugs: VEGF(R) Inhibitors (Bevacizumab, Sunitinib, and Sorafinib)
Will cause do to lack of BV growth/devo:-HTN
-Protein losing nephropathy
-Wound healing compromised

Accelerated aging with chemo due to…
*Cancer cells over express Telomerase-> Inhibit enzyme in both cancerous and normal cells-> decreasing telomerase activity= AGING*
Pregnancy and chemotherapy

Can use but avoid 1st trimester

-Not methotrexate-> can cause abortion
>Avoid antimetabolites

Thromboembolic Disease
*Cancer is thrombogenic*
-Trousseau’s sign of malignancy (blood clot in unusual places-> migratory thromboembolism)-Certain anti-hormonal agents are also thrombogenic especially *tamoxifen* (preventing estrogen development and proper function)

-Chemotherapy is less predictable re. thrombosis but vasculopathic drugs include 5-FU and cisplatinum

-All patients at HIGH risk

Sexual Dysfunction with chemotherapy
-Decreased libido
-Nausea, mucositis, fatigue
-Cessation of ovulation and azoospermia (alkylators and topoisomerase inhibitors)
Bone health and chemotherapy

Increase osteoporosis:

1.) *Corticosteroids*: Decrease GI Ca+ absorption, increase renal excretion

2.) Aromatase inhibitors ( decrease circulating estrogen)

3.) LHRH agonists/antagonists: DECREASE circulating androgens and estrogen

4.) Most chemo agents to certain degree: Probably hormonal effect

Drugs known to cause arthralgia

1.) Aromatase Inhibitors

2.) Adjuvant Chem (especially for breast cancer)

-Cancer mimics LOW thyroid
-Narcotics mimic LOW thyroid
-Depression mimics LOW thyroid
-TKI’s cause hypothyroidism
-Radiotherapy can cause hypothyroidism (sunitinib, etc)
-Same carrier protein as many chemo agents
-Increases relative dose of each drug-May cause mucosal disruption aggravating chemo induced *mucositis*

-INCREASED bleeding risk


-Same carrier protein

-INCREASED risk of fungal infections

Anti-Gout Medication
-May INHIBIT pro-drug activation
*Allopurinol and 5-FU*-May increase drug effect
*Colchicine and vincas*

*Allopurinol and 6-MP (prevents XO removing 6-MP)*

Increase risk of renal dysfunction when *platinum is used*
-Loss of potassium and magnesium
Induce hepatic metabolism of of *irinotecan* resulting in decreased efficacy

-Warfarin and 5-FU/ capecitabine/ etoposide (Podophyllotoxin) / carboplatinum/paclitaxel/ gemcitabine

-Same carrier protein leading to INCREASED BLEEDING
>Warfarin gets displaced and will remain in body

Cytochrome p-450

Catalyzes oxidation of organic substances for drug metabolism and bioactivation

-Increase activity: Antiepileptic drugs

-Decrease activity: Grapefruit Juice

-Unpredictable: St John’s Wort


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