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2. Trimetrexate
Principles of Cancer Chemotherapy - antimalarial agent, also a potent inhibitor of DNHFR
Goal of treatment
A. Cure – eradication of every neoplastic cell
B. Palliation – alleviation of symptoms and avoidance of life 3. 6 – Mercaptopurine
threatening toxicity - the thiol analog of the purine hypoxanthine. It is converted
to the corresponding nucleotide – 6-thioinosinic acid 6 T-
Tumor susceptibility and the growth cycle IMP which inhibits the formation of adenine and guanine
4 Phases of the Cell Cycle from Inosinic monophosphate (IMP).
1. M phase – period of mitosis (cell division) - Fate: 6 MP is converted to thiouric acid in the liver (this
2. G1 phase – interval during which RNA, protein synthesis and reaction is catalyzed by xanthine oxidase)
cellular growth occurs
3. S phase – DNA synthesis
4. G2 phase – synthesis of cellular components required for
mitosis
5. Go- resting state where cell is not dividing
4. 6- Thioguanine (6 TG)
- MECH = converted to 6 –thioguanine 5 Phosphate (6-thio-
GMP) which replace guanine nucleotide and inhibit DNA
synthesis
2. Cell-cycle non specific – agents that are active while the cancer
cells are dividing but whose action spans more than one phase
of the cycle as well as within Go.
• Example: Mechlorethamine, cisplatin, nitrosourceas
• they are effective for both high growth fraction as
well as low fraction malignancies e.g solid tumors
Antimetabolite
a) Folate antagonist : Methotrexate, Trimetrexate
b) Purine derivatives : Mercaptopurine ,Thioguanine
c) Pyrimidine derivative : Fluorouracil (5 FU), Floxuridine,
Cytarabine
1. Methotrexate
Mechanism of Action – competes with folic acid for the active
binding sites on dihydrofolate reductase (DHFR) enzyme
2. CYCLOPHOSPHAMIDE
• A nitrogen mustard that is biotransformed by the hepatic
cychrome p450 into hydroxylated intermediates :
phosphoramide , the active alkylating agent (anti- cancer)
and acrolein which can cause hemorrhagic cystitis
• TOXICITY : hemorrhagic cystitis (prevention of this is by
4. a. Doxorubicin - Are anthracycline antibiotics
vigorous hydration and the use of
(adriamycin)
mercaptoethanesulfonate (mesna))
b. Daunorubicin
-cardiac dysfunction, pulmonary toxicity
Mech. Of Action:
3. CHLORAMBUCIL – SLOWEST ACTING ALKYLATING AGENT
1. Intercalation in the DNA – the drug inserts between
adjacent base pairs and binds to sugar- PO4 backbone
4. IFOSFAMIDE – A DERIVATIVE OF CYCLOPHOSPHAMIDE of DNA, thus blocking DNA synthesis
5. CARMUSTINE (BCNU) AND LOMUSTINE (CCNU) 2. Binds to cell membrane and alters the function of
• ARE NITROSOUREAS WITH HIGH LIPOPHILICITY THAT transport process
FACILITATES CNS ENTRY 3. Generation of Oxygen radicals or superoxide
• USE –TREATMENT OF BRAIN TUMORS
4. Cisplatin
CMF regimen: Cyclophosphamide plus
2. Recruitment and Synchrony – the strategy of recruitment
19. Breast Carcinomamethotrexate& fluoouracil, or doxorubicin involves initial use of CCNS drug to achieve a significant log kill,
(stages I &II) for methotrexate which results in the recruitment into cell division of previously
CAF regimen: tamoxifen if hormone resting cells in the GO phase. With subsequent administration of
receptor positive CCS drug that is achieve against dividing cells.
Syncrony – example the use of vinca alkaloids to holds cancer
20. Breast carcinoma - As above paclitaxel, plus cell in the M phase and subsequent treatment of
(stages III & IV) trastuzumab(if HER2 protein) w/ or another CCS drug such as the S-phase specific
w/o aromatase inhibitors Cytarabine which results in a greater killing effect
on the neoplastic cell population
Dose limiting adverse effects of Chemotherapetic agents
1. Methotrexate - Bone marrow suppression (BMS) 3. Rescue Therapy – use to alleviate toxic effects of anticancer
- oral and GI ulceration drugs.