8. 1.ALKYLATING AGENTS a. Alkylating agents contain chemical groups that produce highly reactive carbonium ion intermediates that can form covalent bonds with particular nucleophilic,substances in the cell. b. These ions are highly reactive with electron donors such as amine,hydroxy and sulfhydryl groups. c. The nitrogen at position 7(N7) of guanine residues in DNA is strongly nucleophilic and is especially susceptible.other molecular sites such as N1 and N3 of adenine and N3 of cytosine may also be effected. d. Most of the alkylating agents are bifunctional(have two alkylating groups) and are able to react with two groups causing intra or inter chain cross linking.
9. e. This can interfere not only with transcription but also with replication.Thus alkylation may result in cross linking,cross scission or abnormal base pairing. f. Alkylating agents mainly exert cytotoxic actions.some of alkylating agents have CNS stimulant,immuno suppressant and cholinergic properties.
10. 2. ANTIMETABOLITES a. Antimetabolites are structurally related to normal componente of DNA or of coenzymes involved in the nucleic acid synthesis. b.These generally interfere with the availability of purine or pyrimidine nucleotide precursors by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. (a) FOLATE ANTAGONISTS METHOTREXATE Methotrexate is the most widely used antimetabolite in cancer chemotherapy . a. It mainly acts by inhibiting the enzyme dihydro folate reductase(DHFR),which is essential in synthesis of folate. b. It is cell cycle specific and kills cells in S phase.
11. c. It mainly inhibits the synthesis of DNA also affects RNA and protein synthesis. MECHANISM OF ACTION 1.folic acid is essential for the production of co enzyme,tetrahydrofolic acid(THF). 2. The conversion of folate to THF is carried out by an enzyme,folate reductase. 3. Methotrexate competes with folic acid for this enzyme by binding irreversibly to folate reductase,thus inhibiting the production of THF. 4. lack of the co enzyme THF leads to inhibition of DNA synthesis and consequently of cell replication.
12. PHARMACOKINETICS 1.Methotrexate is usually administered orally.it can also be given intramuscularly,intravenously. 2.The drug is mainly concentrated in intestinal epithelium,liver,kidney,skin. 3. It is actively taken up by the cells and is metabolized into polyglutamate derivatives,which are retained in cells for long time. ADVERSE EFFECTS 1.Unwanted effects are due to deficiency of folate and include depression of bone marrow and damage to gastrointestinal epithelium. 2. Other unwanted effects include pneumonitis,nephrotoxicity,pulmonary toxicity and neurologic toxicity.
13. CLINICAL USES It is used for the treatment of acute lymphatic leukaemia,choriocarcinoma and other malignancies. It is also used for rheumatoid arthritis,psoriasis and as immunosuppressant
14. (b) PURINE ANTAGONIST 6-MERCAPTOPURINE 6-Mercaptopurine is an analogue of purine and is highly effective anticancer drug. MECHANISM OF ACTION The drug is convorted in the cells to ribonucleotide of 6-mercaptopurine,which then suppresses the denovo biosynthesis of purines and hence of DNA. PHARMACOKINETICS 1. The drug is well absorbed on oral administration. 2. It is distributed well throughout the body except cerebrospinal fluid. 3. It is metabolized to thiouric acid by xanthine oxidase.
15. 4. Mercaptopurine and its metabolites are rapidly excreted by the kidney. ADVERSE EFFECTS 1.Unwanted effects include nausea,vomiting,diarrhoea. 2. Bone marrow depression is the main toxic effect produced and hepatotoxicity is also reported. CLINICAL USES 1. 6-mercoptopurine is mainly used in childhood acute leukaemia,choriocarcinoma and in solid tumours. 2 It is also used in the maintenance of remission in acute lymphoblastic leukaemia.
16. PYRIMIDINE ANTAGONISTS 5-FLUOROURACIL 5-Fluorouracil is an analogue of uracil(pyrimidine). MECHANISM OF ACTION 1. It must be converted in the body to the corresponding deoxynucleotide(5-fluoro-2-deoxy uridine monophosphate),which inhibits thymidylate synthesis and blocks the conversion of deoxyuridilic acid to deoxythymidilic acid. The result is inhibition of DNA synthesis but not RNA or protein synthesis.
17. PHARMACOKINETICS 1. 5-Fluuorouracil is administered intravenously to prevent first-pass metabolism. 2. It is well distributed in the body including CNS. 3. It is mainly metabolized in liver and dosage must be adjusted in impaired hepatic function. ADVERSE EFFECTS 1. Unwanted effects include gastrointestinal disturbances. 2. ulcers in GIT. 3. Bone marrow depression and anorexia. CLINICAL USES The drug is mainly used in solid tumours of breast,colon,urinary bladder,liver etc.
18. VINCA ALKALOIDS Vincristine,vinblastine and vindesine are main vinca alkaloids used in cancer chemotherapy.These are obtained from the plant VINCA ROSEA. MECHANISM OF ACTION These act by inhibiting mitosis.They bind to tubulin and inhibit its polymerization into microtubules and thus prevent spindle formation in mitosing cells and cause arrest of metaphase. Hence,they are both cycle specific and phase-specific. PHARMACOKINETICS 1 . Vinca alkaloids are usually administered intravenously. 2. They are mainly concentrated and metabolized in liver.
19. Excreted into bile and faeces . ADVERSE EFFECTS 1. Common unwanted effects include nausea,vomiting,diarrhoea . 2. Vincristine has mild myelosuppressive activity but causes parasthesias and muscle weakness. 1. Vinblastine is more potent myelosuppressant and less neurotoxic but causes leucopenia. CLINICAL USES 1. Vincristine is mainly used in treatment of childhood acute leukaemia. 2. It is also used in lymphosarcoma,Hodgkin’s disease,wilm tumour.
20. TAXANES PACLITAXEL Paclitaxel is obtained from the bark of western yew tree . MECHANISM OF ACTION The drug reversibly bind to the tubulin and results in formation of stable non-functioning microtubule by promoting polymerization and stabilization of the microtubles. Thus,it interferes with mitosis causing the death of the cell. PHARMACOKINETICS 1.Paclitaxel is administered by intravenous infusion. 2.It is metabolized in liver and is eliminated in bile.
21. ADVERSE EFFECTS 1. Unwanted effects include bone marrow toxicity and cumulative neurotoxicity. 2.skin rashes. 1. Hypersensitivity reaction. CLINICAL USES 1.Paclitaxel is mainly used in metastatic ovarian and breast carcinomas. 2.It is also effective against advanced causes of head and neck cancer,small cell lung cancer.
22. ANTIBIOTICS ACTINOMYCIN D Actinomycin D is very potent antineoplastic antibiotic obtained from the species of STREPTOMYCES. MECHANISM OF ACTION The drug intercalates into the minor groove of double helix between guanine-cytosine base pairs of DNA and interfere with the movement of RNA polymerase along the gene and thus preventing transcription. It may also cause strand breaks and stabilize DNA-topoisomerase II complex.
23. PHARMACOKINETICS 1. Dactinomycin is administered intravenously. 2. It mainly concentrated in the liver.doesnot cross the blood-brain barrier. 3.It is partially metabolized in liver. 1. Excreted in bile and urine. ADVERSE EFFECT Vomiting Stomatitis Diarrhoea Bone marrow depression. It can damage the skin that is exposed to radiation.
24. CLINICAL USES It is used in the combination with surgery and vincristine for the treatment of wilm’s tumour and soft tissue sarcomas. MISCELLANEOUS DRUGS HYDROXY UREA M.O.A. Hydroxyurea is acts by blocking the conversion of ribonucleotides by inhibiting the enzyme ribonucleoside diphosphate reductase,a rate limiting step in DNA synthesis. ADVERSE EFFECT Myelosuppression Gastrointestinal disturbances
25. Alopecia Stomatitis CLINICAL USES Treatment of chronic granulocytic leukaemia. Thrombocytosis some solid tumours. RADIOACTIVE ISOTOPES Radioactive isotopes are used in the treatment of certain tumours by their property of producing ionization in the cells,thereby causing cell destruction. 1.Radioactive Iodine is used in thyroid carcinoma. 2.Radioactive phosphorus is used in polycythemia vera.
26. 3.Radioactive Gold is used in palliative treatment of malignant pleural and peritoneal effusions. MONOCLONAL ANTIBODIES Monoclonal antibodies such as Rituximab and Trastuzsumab are also use in the cancer chemotherapy. This antibodies activate the host immune mechanism and kills the cancer cells. Rituximab is used for Bita cell lymphoma and Trastazumab is used for breast cancer treatment.
27. TREATMENT PROTOCOLS Treatment with combination of anticancer drugs is more effective than monotherapy without increasing toxicity. Combination chemotherapy also decreases the possibilith of the development of resistance to individual agents. Combination chemotherapy can be useful in achiving higher responsive rates due to both additive or potentiated cytotoxic efferct and non-overlapping host toxicities. Some combination….. POMP : methotrexate+ oncovin(vincristine)+ prednisone+ purinethol(mercaptourine) used in Lymphocytic leukaemia.
29. CHEMOTHERAPEUTIC AGENTS AFFECTING THE AVAILABILITY OF RNA AND DNA PRECURSORS. PURINE AND PYRIMIDINE SYNTHESIS RIBO-NUCLEOTIDES DEOXYRIBO-NUCLEOTIDES DNA RNA PROTEINS
