Pharmacology: Antineoplastic Agents, Cell-Cycle Non-Specific Drugs (CCNS)

Classes of Drugs:
Classes of Drugs:
-Cell Cycle Specific Drugs (CCS)
-Cell Cycle Non-Specific Drugs (CCNS)

Toxicity of Cancer Chemotherapeutic Agents:
-Acute Toxicity: Occurs within *hours.*
-Delayed Toxicity: Occurs within *Days or Weeks.*
-CCS Drugs
–Antimetabolites:*No acute toxicity.*
–*Antimitotics: acute and delayed toxicity.*
-*CCNS Drugs
–Acute and chronic toxicity.
–Side effects more severe.*

Cell Cycle Non-Specific Drugs:
Cell Cycle Non-Specific Drugs:
-Alkylating Agents
-Antibiotics
-Cisplatin and other Metal Compounds
-Hormones
-Enzymes
-New CCNS Drugs

Mechanism of Action of CCNS (Cell Cycle Non-Specific) Drugs:
-Many act as DNA modifying agents producing *DNA lesions and DNA damage.*
-Will affect both non-cycling and cycling cells.
-Hammer

Side Effects of CCNS (Cell Cycle Non-Specific) Drugs:
-severe
-acute and chronic toxicity

Classes of Alkylating Agents:
1. Nitrogen Mustards (Chlorambucil, cyclophoasphamide)
2. Alkyl Sufonatates (Busulfan)
3. Ethylenimines (Thiotepa)
4. Triazines (Decarbazine)
5. Tetrazines (Temozolomide)
6. Nitrosureas (Carmustine, Iomutsine, Streptozocin)

There are a variety of alkylating agents, all with distinct __________ differences. Many require ____ metabolism to active drug.
There are a variety of alkylating agents, all with distinct *structural* differences. Many require *host* metabolism to active drug.

General Mechanism of Action of alkylating agents:
General Mechanism of Action of alkylating agents:
-Agents all act by *alkylating macromolecules, notably DNA*; and/or by *forming covalently-bound cross-links in DNA.*

General toxic side-effects of alkylating agents:
General toxic side-effects of alkylating agents:
acute and chronic
–nausea and vomiting
–bone-marrow suppression
–alopecia
–teratogenicity
–carcinogenicity
–cross-resistance occurs between many of these agents.

DNA Alkylation
Either a methyl or ethyl group is added and can *disrupt nucleotide base pairing, causing mutations.* This is goingt to mess up the cell.

Alkylation Agents in Cancer Chemotherapy:
Alkylation Agents in Cancer Chemotherapy:
-*Cyclophosphamide* (Cytoxan): CHOP, CMF, CAF, lymphoma, leukemia, *breast cancer.*
-*Busulfan*: leukemia.
-Thiotepa: ovarian cancer.
-Decarbazine: Melanoma.
-*Temozolomide*: Glioma.
-Carmustine: brain cancer.

Antibiotics:
Antibiotics:
-Actinomycin D (dactinomycin)
-Bleomycin
-Doxorubicin (adriamycin)
-Daunorubicin

Anthracyclines:
Anthracyclines:
-Daunorubicin
-Doxorubicin

Mechanism of Action of Anthracyclines:
-*Single- and double-stranded breaks* occur
–Mediated by drug *binding to DNA and topoisomerase II.*
-Can also generate *free radicals.*
-Cell exposure leads to *apoptosis*: we want this to happen.

Daunorubicin, Therapeutics:
Daunorubicin, Therapeutics:
-Useful in treatment of *acute lymphocytic and acute myelogenous leukemias.*
-Severe local vesicant action can occur.
*-May impart a red color to urine.*

Daunorubicin, Clinical Toxicities:
-Bone marrow depression.
-Stomatitis.
-Alopecia.
-GI disturbances.
-Dermatological manifestations.
*-Cardiac toxicity: peculiar adverse event observed with these agents. Effects normal heart function.* (ask cardiologist if you can use this drug on a patient.)

Doxorubicin (Adriamycin), Therapeutics:
*-Effect in acute leukemias and malignant lymphomas.*
-In contrast to daunorubicin, is active in a number of *solid tumors (breast cancer).*
-Severe local vesciant action can occur.
-*May impart a red color to urine.*

Doxorubicin, Clinical Toxicities:
Doxorubicin, Clinical Toxicities:
-Similar to daunorubicin.
-*Erythematous streaking near site of infusion (Adriamyacin flare).*
*-Cardiomyopathy.*

St. John’s Wort:
-Herbal medicine used to treat depression.
-*Binds to topoisomerase II.
-Competitive antagonist to daunorubicin and doxorubicin.
-Contraindicated during cancer treatment with either drug.*
-Case History.

Actinomycin D, Mechanism of Action:
-Intercalates into DNA.
*-Blocks transcription of DNA by RNA polymerase.*

Actinomycin D, Therapeutic Uses:
-Childhood neoplasms.
-Soft tissue sarcomas (Ewing’s and Kaposi’s).
-Also used to inhibit immunological responses (e.g. renal transplants).

Actinomycin D, Toxicities:
-Nausea and vomiting.
-Allopecia.
-Reduction in bone marrow function.
-Loss of appetite.
-Others: dysphagia, rashes/acne, mouth sores, fever, diarrhea, temporarily altered liver function.

Bleomycin, Mechanism of Action:
-A DNA-cleaving antibiotic.
-Can cause oxidative damage to DNA leading to single- and double-stranded breaks in DNA.

Bleomycin, Therapeutic Uses:
-Highly effective against *germ cell tumors of the testis and ovary.*
-Can be used in combination therapy in squamous carcinomas of the head, neck and esophagus as well as in Hodgkin’s and non-Hodgkin’s lymphoma.

Bleomycin, Clinical Toxicities:
-Little myelosuppression.
*-Significant cutaneous toxicity.
-Significant pulmonary toxicity.*
-*Toxicities do not overlap with other drugs.*

Cisplatin, Therapeutic Uses:
Cisplatin, Therapeutic Uses:
*-Used for the treatment of ovarian cancer.*
-Results in *renal, hearing and neurological toxicity.*
-Hydration recommended.
-Combination therapy with *bleomycin, etoposide, and vinblastine for advanced testicular cancer.*

Carboplatin:
Carboplatin:
-*Similar mechanism to cisplatin.
-Less nausea, neurtoxicity, ototoxicity, and neurotoxicity.
-Dose limiting toxicity is myelosuppression primarily evident as thrombocytopenia.*
-Effective alternative for patients with responsive tumors who are *unable to tolerate cisplatin because of impaired renal function.*
-Approved for use in combination with paclitaxel or cylcophosphamide in patients with advanced ovarian cancer.

Arsenic Trioxide:
-Used for the treatment of acute promyelocytic leukemia.
-Mechanism:*induces differentiation and apoptosis.*
-Side effects: *Lightheadedness during infusion, fatigue, musculoskeletal pain, hyperglycemia and peripheral neuropathy.*

The selective estrogen receptor modulator __________ has become first-line therapy for the hormonal treatment of breast cancer.
The selective estrogen receptor modulator *tamoxifen* has become first-line therapy for the hormonal treatment of breast cancer.

Tamoxifen:
Tamoxifen:
-Competitive inhibitor of estradiol binding to the estrogen receptor (ER).
-When bound to the ER, tamoxifen induces a change in the 3D shape of the receptor, inhibiting binding of the estrogen responsive element on DNA.

Tamoxifen, Therapeutic Use:
Tamoxifen, Therapeutic Use:
-Endocrine treatment of choice for postmenopausal women with estrogen-receptor positive breast cancer.
-Usually prescribed for 5 years (development of uterine tumors).

Tamoxifen, Clinical Toxicity:
Tamoxifen, Clinical Toxicity:
*-Hot flashes.
-Nausea and vomiting.
-Weight gain.
-Endometriosis.
-Blood-clotting abnormalities.
-Depression, tiredness and dizziness.*

Dexamethasone (and Prednisone):
-Used in conjunction with x-ray therapy to reduce edema related to tumors in tumors in the brain and spinal cord.
-Antitumor effects are mediated by binding to a specific cytoplasmic receptor, which when activated, induces a program of gene expression that leads to *apoptosis.*
-Takes time, it is not instantaneous.

(Enzyme) Asparaginase:
-Action:*deprives certain leukemic cells of the essential metabolite, asparagine.*
-Side effects: acute: can cause fever; chronic: can include mental depression (coma in extreme cases) and hepatotoxicity.

New Therapies:
-Aromatase Inhibitors
-Trastuzamab (herceptin)

Aromatase:
-Enzyme which produces estrogen from androgens.
-Estrogen synthesis occurs in the ovary and the adrenal gland.
-After menopause, *synthesis only in the adrenal gland.*

Aromatase Inhibitors:
Aromatase Inhibitors:
*-Anastrozole, Letrozole.*
-Non steroidal drugs which *inhibit aromatase.*
-Initially used only in patients who were *estrogen receptor negative (ER-).*
-*Starting to replace tamoxifen* in breast cancer treatment in many postmenopausal women independent of ER status.
-Toxicity not as great as tamoxifen and is as effective.

Trastuzumab (herceptin):
Trastuzumab (herceptin):
-A *monoclonal antibody against the Her2* protein (the type 2 EGFR), which is overexpressed in 25-30% of breast cancer.
-Expression of this protein is associated with decreased survival due to more aggressive disease.
*-Mechanism of action: cell cycle arrest via anti-body mediated cytoxicity.*
-Used in Her2+ breast cancer patients in combination with Paclitaxel.
-Toxicity: *Diarrhea and hematologic effects are most common.*

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