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DR. F. O.

WANGO

Antimetabolites act on nucleotide and nucleic acd synthesis Methotrexate is an example. It is folic acid antagonist and binds to the active site of dihydrofolate reductase. This interupts the synthesis of thymidylate, purine nucleotides and amino acids, serine and methionine, thereby interfering with DNA, RNA and protein synthesis.

Intracellular formation of polyglutamate derivatives appears to be important in the therapeutic action of methotrexate. It can be given orally, intrathecally and intravenously. It is readily absorbed orally in doses less than 25mg/m2 but in high doses it is incompletely absorbed. Approximately 50%is protein bound and 90% is excreted unchanged in urine.

Therapeutic Uses: (1) Psoriasis (2) Rheumatoid Arthritis (3) Acute Lymphoblastic Leukemia. PURINE ANTAGONISTS: Both 6-mercaptopurine and 6-thioguanine are excellent substrates for hypoxanthine guanine phosphoribosyl transferase (HGRRT). They cause marked inhibition of DNA synthesis.

Both mercaptopurine and thioguanine are both given orally and excreted mainly in the urine. Mercaptopurine is inactivated by enzyme xanthine oxidase ( which is inhibited by allopurinol). Fludarabine is given parenterally and excreted mainly in urine.

It is used in treatment of lympho-proliferative diseases. CLADRIBINE: Causes DNA strand breakages through interference with DNA repair. It is recommended for treatment of hairy cell leukemia.

FLUOROURACIL- 5FU. It undergoes biotransformation to ribosyl and deoxyribosyl nucleotide metabolites. One of its metabolites inhibits thymidylate synthase, hence preventing formation of thymine nucleotides. Cytotoxicity is due to its inhibition of both DNA and RNA. It is normally given parenterally since oral route has unprictable and incomplete absorption. Its half life (T1/2) is very short.

Metabolic degradtion occurs in many tissues particularly the liver. It is degraded by dihydropyrimidine dehydrogenase. 5-Fluorodeoxyuridine- FUDR is similar to 5-FU. 5-FU is used for treatment of various adenocarcinomas while 5-FUDR is mainly used in metastatic adenocarcinoma to the liver through hepatic artery infusion.

Toxicities: myelosuppression and mucosities. CAPECITABINE: It is given orally and normally converted to 5-FU. It is mainly excreted through the kidney. It is used in treatment of metastatic breast cancer. Toxicities include myelosuppression, hand and foot syndrome, nausea and vomitting.

S-phase specific antimetabolite. Its metabolites inhibit DNA polymerase. This results in blockade of DNA synthesis while RNA and protein formation continues. It is highly schedule specific due to its s-phase specificity. It is a parenteral drug which is used mainly for Acute Myelogenous Leukemia.

GEMCITABINE: Inhibits DNA synthesis through termination of DNA strand. It is given intravenously by infusion and excreted in the urine. Myelosuppression is the principal dose-limiting toxicity.

Also called vinca alkaloid. VINBLASTINE: mechanism of action involves depolymerization of microtubules and hence mitotic arrest at metaphase. There is dissolution of the spindle and interference with chromosome segregation. Toxicity includes nausea, marrow depression and alopecia. Used mainly in Hodgkins disease and other lymphomas.

VINCRISTINE: Similar to vinblastine. Used mainly in leukemia and rapidly proliferating neoplasms. VINORELBINE: Semisynthetic vinca alkaloid. Used mainly in treatment of advanced non-small cell lung cancer. Toxicity: Granulocytopenia.

ETOPOSIDE AND TEMIPOSIDE. Inhibit topoisomerase 2 which leads to DNA damage. They are given parenterally, protein bound and distributed throughout the body except to the brain. Excretion is through the kidney. Used mainly in: Testicular cancer, oat cell carcinoma and monocytic leukemia.

Acts as mitotic spindle poision through the enhancement of tubulin polymerization. They are given parenterally through infusion. Metabolism is through the liver and less than 10% of the dose is excreted through the urine intact. Toxicities: Thrombocytopenia, Neutropenia and neuropathy. Used mainly in ovarian and breast cancer. Toxicities: Neuropathy Thrombocytopenia neutropenia They are give parenterally through infusion. Metabolism is through the liver and lens than 10% of the dose is expected through the urine infact.

Dactimomycin (Actinomyccin D) Intercalates between base pairs of DNA-(guaninecytosine). This prevents the transcription of DNA by RNA Polymerase. It inhibits rapidly proliferating cells of normal and neoplastic origin and it is one of the most potent antitumour agents known. Given parenterally, eliminated through bile and urine T 36 hrs. It does not cross the blood-brain barrier.

Alopecia, pancytopenia, proctitis, Diarrhoea, Glossitis, Chelitis ulceration of oral mucosa.

Daunorubicin ,Doxorubicin, Epirubicin, Idarubicin and Mitoxantrone. These are anthracycline Antibiotics. They intercalate with DNA, directly affecting transcription and replication. They also form tripartite complex with topoisomerase II and DNA. Topoisomerase II function allows for DNA replication and repair. They are all administered parenterally, metabolised in the liver and excreted in the bile. An alcohol form is an active metabolite, a glycine form is inactive. Toxicity: cardiotoxicities, >550mg/m2 -Bone marrow

An antibiotic which is a mixture of different glycopeptides , major being bleomycin A2 and B2. It binds DNA, resulting in single and double-strand breaks following free radical formation. It is CCS and causes accumulation of cells in G2. It can be given Subcutaneously Intrasmuscularly Intravenously T 2.5hrs Adverse effects (a) Lethal anaphylactoid reaction (b) Blistering and hyperkeratosis of palms (c) Pulmonary fibrosis It does not cause significant bone marrow suppression.

Steroid Hormones and antisteroids. Some tumours depend on hormones for their growth e.g breast and prostate cancers. Adrenal corticisteroids cause dissolution of lymphocytes, regression of lymph nodes and inhibition of growth of certain mesenchymal tissues.

Anti-Estrogen: Selective Estrogen-Receptor modulatorsSERMS e.g Tamoxifen. Binds to estrogen receptor and exerts either estrogen or antiestrogenic effects depending on the specific organ. Anti-estrogen effects are manisfested in breast while estrogenic effects are noted in uterus, coagulation system, liver function and bone metabolism. The drug is absorbed orally and has terminal T of 7 days. Excretion is mainly through the stool. Toxicities: Menstrual irregularities. Endometrial cancer in post-menopausal women. Pruiritus vulvae. Dermatitis. Vaginal bleeding. Toremifene: Similar to tamoxifene

Selective Estrogen-Receptor DownregulatorsSERDS Pure Anti-estrogen, they are devoid of estrogen activities. Fulvestrant: Binds to ER. Given parenterally, once/monthly T is approximately 40 days. Undergoes metabolism in the liver.

Aromatase enzyme converts androstenedione and testosterone to estrogen,estrone and estradiol. Aromatase Inhibitors are either steroidal on nonsteroidal. They are further classified as:(1) First, second and third generations. Examples: Aminogluteflumide-1st generation. Formestane, Rogletimide and Fadrozole - 2nd generation. Anasprozole,letrozole and exemestane are 3rd generation A Is.

Gonadotropin-Releasing Hormone Agonist and Antagonist. GnRH agonists cause an initial surge in levels of LH and FSH followed by inhibition of gonadotropin release. This results in reduction of testosterone. Examples: Leuprolide, Gozerelin Triptorelin Buserelin

(1) (2) (3)

Protein kinases participate in signal transduction pathways that transmit information concerning extracellular or cytoplasmic condition to the nucleus. Examples: Imatinib. Gefitinib (EGFR) antagonist. Erlotimib used in treatment of non-small cell lung cancer.