Anti Malign Ants

Antimalignants 1) 2) 3) 4)

Antimetabolites Alkylating agents Cytotoxic antibiotics Natural Products a. Vinca alkaloids b. Epidophyllotoxins c. Camptothecin d. Taxanes 5) Hormones and Antihormones a. Estorgens b. Antiestrogens c. Androgens d. Antiadnrogens e. Progestins f. Gonadotropin releasing hormone g. Adrenocorticoids 6) Immunosuppressents 7) Miscellaneous a. Enzymes b. Biological response modifiers c. Platinum coordination complexes d. Substituted urea e. Aromatase inhibitor (breast cancer) 1) Antimetabolites

Methotrexate MOA Blocks the enzyme dihydrofolate reductase (DHFR) in the synthesis of purines and pyrimidines and therefore inhibit cell replication. DHFR is responsible for the reduction of folate to tetrahydrofolate which is a 1 carbon carrier. - CCS – works in the S phase of cell cycle Indications - Treatment of malignancies (specifically for dividing cells) Contraindications/Adverse Effects - Potentially Nephrotic at high doses - May be toxic if Pt had ascites due to storage of drug - Myelosuppression – neutropenia, thrombocytopenia, mucositis, diarrhea - Pulmonary and hepato- toxicities if given long term

Note -

causes a build-up of TOXIC intermediate FH2 polyglutamate.

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Calcium Leucovorin is an antidote to drug. Host cells are rescued while cancer cells are less effected by the antidote. (due to level of polyglutamation of Methotrexate in the cells) Filgrastim (Granulocyte growth factor G-CSF) has shortened periods of leucopenia after high doses of chemotherapy

5-Fluorouracil, (Floxuridine) MOA Inhibition of the enzyme thymidylate synthase preventing cells from incorpating thymine into their DNA. Therefore they suffer a “THYMINE-LESS DEATH” Indications - Metastatic carcinoma of the breast - Carcinoma of GI - Hepatoma - Carcinoma of ovary, bladder, prostate, pancrease, oropharynx - Metastatic carcinoma of the colon (Floxuridine) Contraindications/Adverse Effects - Anorexia and nausea - Stomatitis and diarrhea - Myelosuppression (bolus doses) - Alopecia (hair loss) - Effects tumor cells and normal cells equally

Cytarabine (cytosine arabinoside) MOA Cytarabine (araC) is incorporated into cellular DNA and prevents elongation of DNA strand as well as interfering with template function. (ONLY DNA synthesis is inhibited, not RNA or protein synthesis) Indications - Acute myelocytic leukemia (AML)

Azathioprine Mercaptopurine Fludarabine MOA (CCS) 1) Prevents clonal expansion of B and T lymphocytes by conversion to nucleotide 6-thioinosinic acid causing inhibition of purine nucleotide interconversions 2) Prevents de novo purine synthesis by inhibiting PRPP Synthetase and PRPP amidotransferase enzymes while drug is in nucleotide format. Blocking purine synthesis 3) Inhibits DNA formation by false substrate action (salvage pathway) Indications - PREVENT graft rejections by lowering immune response

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Treatment of autoimmune diseases (Crohn’s, RA) Treatment of delayed hypersensitivity reactions Treatment of various malignancies

Contraindications - individuals who are already immuno-compromised Notes - highly inactivated by liver, therefore IV dosage - causes bone marrow suppression - drug interactions with allopurinol causes toxic levels of mercaptopurine (intermediate) due to competition for enzyme  allopurinol preferentially binds to enzyme

Pentostatin MOA Blocks the enzyme adenosine deaminase (ADA) which is essential in two steps of DNA synthesis. (adenosineinosine and deoxyadenosinedeoxyinosine) Indications - Treatment of Hairy Cell Leukemia 2) Alkylating Agents

Cyclophosphamide (Ifosphamide) MOA (CCNS) Become strong electrophiles through the formation of cabonium intermediates which bond with nucleophiles, like the N7 of guanine, and causes abnormal base-pairings and breakage. Pro-drug converted in the liver to a active nitrogen mustard which, together with acrolein are end products of metabolism Indications - Chronic lymphatic leukemia - SOLID tumors - Non-Hodgkin’s lymphoma - Ovarian carcinoma - Neuroblastoma - Immunosuppressive Contraindications/Adverse effects - Active mustard is VERY nephrotoxic - Acrolein causes chemical cystitis (hemorrhagic) - Myelosuppressive with less severe thrombocytopenia - Permanent amenorrhea and azoospermia - Leukemogenic - Renal and bladder toxicity - GI toxicity due to denudation - Pulmonary fibrosis Note -

Give IV, Pro-drug that needs conversion

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Give with HIGH WATER DOSES to prevent reabsorbtion in the nephron MESNA is antidote which conjugates toxic metabolites like acrolein in the urine Inappropriate secretion of ADH (not enough) will cause water-intoxication (give demeclocycline to block effects of ADH)

Bulsulphan MOA (CCNS) Selective depression of granulocytopoesis. Indications - Treatment in Chronic Myelogenous Leukemia (CML) - Treatment in Acute Myelogenous Leukemia (AML) Contraindications/Adverse effects - Busulphan lung – pulmonary fibrosis - Busulphan tan – hyperpigmentation - Adrenal suppression (can’t deal with stress) - Thrombocytopenia

Carmustine MOA Enters brain and forms cross-linkages in the DNA chains causing abnormal base-pairing and DNA breakage. Indications - Malignant astrocytomas and metastatic tumors of the brain 3) Cytotoxic Agents

Doxorubicin MOA (CCNS, CCS) Acts as a topoisomerase poison by integrating into the DNA and binding to the helical groove preventing the topoisomerases from resealing helical breaks. Also causes free radical formation which are damaging to the cells. Indications - Solid tumors of breast, endometrium, testes, lung - ABVD in Hodgkin’s Disease - CHOP in Hodgkin’s Lymphoma - Sarcomas – osteogenic, Ewing’s, soft tissue - Metastatic carcinoma of the thyroid Contraindications/Adverse effects - RESISTANCE may occur due to the active outward pumping of the drug - Sever cardiomyopathy may occur - Erythematous streaking at site of infusion - Myelosuppression - Alopecia Note - Must be given by FAST RUNNING IV to prevent extravasation

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Dexrazoxane, an iron chelator, is the antidote that may prevent cardiac damage Dimethyl sulphoxide is antidote to prevent free radical ulceration Both mutagenic and carcinogenic Enhanced doxorubicin toxicity is seen with azathioprine

Daunorubicin MOA (mainly CCNS) Acts as a topoisomerase poison by integrating into the DNA and binding to the helical groove preventing the topoisomerases from resealing helical breaks. Also causes free radical formation which are damaging to the cells. Indications - Treatment of Leukemia Contraindications/Adverse effects - May cause red urine

Dactinomycin MOA Binds to DNA helix and prevents the transcription of the strand by RNA polymerase. It may also cause single strand breaks in the DNA probably through free radical formation. Indications - Rhabdomyosarcoma - Wilm’s rumor in children - Ewing’s tumor - Kapsoi’s sarcoma Contraindications/Adverse effects - hematopoietic suppression - Pancytopenia – dose limiting property - Proctitis, diarrhea, glossitis, cheilitis and ulcerations of oral mucosa - Alopecia, anorexia, nausea, vomiting

Bleomycins MOA Causes fragmentation of DNA and cells accumulate in the G2 phase of the cell cycle prevented from going forward. (mixture of two copper chelating peptides) Indications - Testicular caners - Squamous carcinomas of the head, neck, lungs - Lymphomas

Contraindications/Adverse effects - VERY LITTLE myelosuppressions

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Pulmonary toxicity (dry cough) Pulmonary Fibrosis Hyperthermia Skin blisters, pigmentation, hyperkeratosis

4) Natural Products a. Vinca alkaloids

Vincristine MOA (CCS) Spindle poison. Bind to tubulin and prevent assembly of microtubules. (Act in M phase) Indications - Pediatric Leukemias - Solid tumors (Hodgkin’s Disease) - Rhabdomyosarcoma - Lymphomas - Neuroblastoma Contraindications/Adverse effects - Peripheral neuropathy - Relatively bone marrow sparing Note -

Christ my nerves!!!

Vinblastine MOA (CCS) Spindle poison. Bind to tubulin and prevent assembly of microtubules. (Act in M phase) Indications - Hodgkin’s (ABVD) - Testicular carcinoma (VBC, VBE) Contraindications/Adverse effects - Myelosuppressive - Leucopenia - alopecia Note -

Blast my bones!!! b. Epidophyllotoxins

Etoposide MOA Stablilises the topoisomerase II-DNA complex causing double strand DNA breaks during DNA replication. (S and G2 phases only) Indications - Testicular carcinoma

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Diffuse lymphoma Hodgkin’s Disease Oat cell carcinoma of lung

Contraindications/Adverse effects - Dose limiting leukemia - Anaphylaxis - Hepatic toxicity at high doses c. Camptothecins

Topotecan MOA Topoisomerase 1 inhibitor causing single strand breaks in DNA. Indications - Colorectal, Ovarian, and small cell cancers Contraindications/Adverse effects - dose limiting neutropenia and thrombocytopenia d. Taxanes

Paclitaxel Docetaxel MOA Prohibit microtubule disassembly causing microtubular plates to accumulate and dysfunctional spindles. Indications - Ovarian Cancer - Breast Cancer Contraindications/Adverse effects - Hypersensitivity reactions - Neutropenia - Alopecia - Cardiac arrhythmias (asymptomatic) - Peripheral neuropathy (Paclitaxel) - Damage to nails and fluid retention (Docetaxel) Note -

Paclitaxel clearance is reduced with combined use of cisplatin causing toxicity.

5) Hormones and Antihormones Tamoxifen (Antiestrogen) MOA Prevents estrogen from binding to estrogen receptors. Indications - Breast cancer treatment and prophylaxis

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Infertility Gynecomastia Older women with inoperable tumors

Contraindications/Adverse effects - Hot flashes - Vaginal bleeding - Hypercalcemia - Peripheral edema

Flutamide (Antiandrogen) MOA Inhibits the translocation of steroid receptors to the nucleus. Non steroidal Indications - Prostatic cancers

Cyproterone (Antiandrogen) MOA Steroidal Androgen Receptor Agonist. Blocks receptors of testosterone on the prostate as it blocks intracellular receptors for dihydrotestosterone. Indications - Prostatic cancers

Leuprolide (Gonadotrophin releasing hormone) MOA Acts as partial agonist at the GnRH receptors and may inhibit release of LH and FSH at constant doses. Indications - Prostatic Carcinoma Contraindications/Adverse effects - Bone and back pain - Gynecomastia - Hematuria - Impotence - Testicular atrophy 6) Immunosuppressives (see Immunosuppressive Outline) 7) Miscellaneous

Asparaginase MOA Hydrolyses L-asparagine to ammonia and aspartic acid, thus depriving the cancer cell of the amino acid asparagines for protein synthesis causing the cell to go through apoptosis. Indications - Acute lymphoblastic leukemia

Contraindications/Adverse effects - Hypersensitivity reactions - Toxic to CNS at high levels

Cisplatin MOA Diffuses into cell and chloride molecule is replaced by a water molecule activating drug. Compound then reacts with DNA causing inhibition of replication and transcription by DNA breaks and miscoding. Cell cycle phase differs with different cell types. Indications - Urinogenital cancers Contraindications/Adverse effects - Nephrotoxicity - Electrolyte disturbances - Nausea and vomiting Note -

RAPID INJECTION and FLUSHING Vigorous hydration

Drug Combination Therapies Breast Cancer CMF

Cyclophosphamide Methotrexate 5-Flurouracil

Pancreatic Cancer

FAM

5-Flurouracil Doxorubicin (Adriamycin) Methortrexate

Ovarian Cancer

CP

Cyclophosphamide CisPlatin

Testicular Cancer

PVB

CisPlatin Vinblastine Bleomycin

Non-Hodgkin’s Lymphoma CHOP

Cyclophosphamide Doxorubicin (Hydroxydaunorubicin) Vincristine (Oncovorin) Prednisone

Hodgkin’s Disease

MOPP

Hodgkin’s Disease

ABVD

Mechlorethamine Vincristine (Oncovorin) Prednisone Procarbazine Doxorubacin (Adrianmycin) Bleomycin

Vinblastine Dacarbazine 1) Antimetabolites Methotrexate 5-Flurouracil (Floxuridine) Cytarabine Azathioprine Mercaptopurine Fludarabine Pentostatin 2) Alkylating agents

3)

4)

5)

6) 7)

Cyclophosphamide (Ifosphamide) Bulsulphan Carmustine Cytotoxic antibiotics Doxorubicin Dactinomycin Dactinomycin Bleomycins Natural Products a. Vinca alkaloid Vincristine Vinblastine b. Epidophyllotoxins Etoposide c. Camptothecin Topotecan d. Taxanes Paclitaxel Docetaxel Hormones and Antihormones a. Antiestrogens Tamoxifen b. Antiadnrogens Flutamide Cyproterone c. Gonadotropin releasing hormone Leuprolide Immunosuppressents Miscellaneous a. Enzymes Asparaginase b. Biological response modifiers c. Platinum coordination complexes CisPlatin