Chemotherapy Flashcards
Gompertzian Model of Growth
Gompertzian Model of Growth
Growth–Growth rate of tumor cells decreases with time
Response to chemotherapy is during rapid growth phase.
Skipper-Schabel model of tumor growth
Skipper-Schabel model of tumor growth. Simply stated:
One living leukemic cell can be lethal to the host; therefore, to cure experimental leukemia, it will be necessary to kill every leukemic cell in the mouse, regardless of the number, anatomic distribution, or metabolic heterogeneity, with treatment that spares the host.
The percentage, not the absolute number, of in vivo leukemic cell populations of various sizes killed by a given dose of a given drug is reasonably constant. The phenomenon of a constant fractional (or percentage) drug kill of a cell population, regardless of the population size, has been observed repeatedly.
The percentage of experimental leukemic cell populations of any size killed by single-dose treatment of drug to the host is directly proportional to the dose level of the drug (i.e., the higher the dose, the higher the percentage cell kill).
Goldie-Coldman
Goldie-Coldman
A fraction of tumor cells will develop resistance after treatment.
This clone will continue to grow even though the patient appears to respond.
Alternating combinations of chemotherapy agents early in treatment is necessary to prevent development resistant clones.
Types of Chemo
ADJUVANT CHEMOTHERAPY
Adjuvant chemotherapy may be given after potentially curative treatment:
Surgery e.g. Breast cancer.
Radiotherapy e.g.Lymphomas/Leukaemias.
Neoadjuvant chemotherapy
Administration of chemotherapy to shrink a tumor before it is removed surgically.
e.g. colo rectal and gynaecological cancers.
Induction therapy
Therapy given as the primary treatment for a disease.
e.g. Leukemias and Lymphomas.
Palliative
Symptom Control i.e. pain control when previous therapy has failed or disease has relapsed.
Combination Therapy
COMBINATION THERAPY
Goals
Maximum cell kill with tolerable toxicity.
Broad coverage of resistant cell lines.
Prevent development of resistance.
Method
Use only effective drugs.
Use optimal scheduling and dose.
Limit overlapping toxicities.
Disadvantages
Multiple toxicities.
Reduction or holding of doses due to toxicity will limit effectiveness.
Complicated to administer.
Expensive
Alkylating Agents
Alkylating Agents
MOA: Bind to DNA causing breaks
Alkylate with DNA at N7 coding position of guanine
Miscoding through abnormal base-pairing with thymine or in depurination by excision of guanine residues, leading to strand breakage
Cross-linking of DNA and ring cleavage may also occur
Cell Cycle Non-Specific.
Major Toxicity: Myelosuppression, alopecia.
Examples:
- Busulfan -alkyl sulfonate
- Cyclophosphamide : nitrogen - mustards
- Melphalan
- Nitrosureas :
Carmustine - brain tumours
MOA: Exerts its effect due to both alkylation of DNA and carbamylation of lysine residues on proteins.
Can cross blood brain barrier due to high lipid solubility
Antibiotics
Anthracycline Antibiotics
DACTINOMYCIN OR ACTINOMYCIN D
1. Intercalates in DNA minor grooves between adjacent GC pairs.
2. Preventing elongation by RNA polymerase and inhibits transcription.
3. Also Inhibits topoisomerase II.
MOA:
1. Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells.
2. Inhibits topoiosomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication.
3. Creates free oxygen radicals that damage the DNA and cell membranes.
4. Cell cycle non-specific.
Side effects: cardiotoxicity due to free radical production, alopecia.
Platinum Analogues
Eg cisplatin
MOA: They coordinate to DNA to interfere with DNA repair.
Forms both interstrand and intrastrand crosslinks in DNA, RNA.
Cell Cycle Non-Specific.
Major Toxicities: Renal and N/V.
Used mainly for treatment of sarcomas, ovarian cancer, lung cancer and lymphomas.
Vinca Alkaloids
Vinca alkaloids: lymphomas and leukemias.
Major Toxicities: Neuropathy, alopecia, hyponatremia, GI tract, myelosuppression.
- Binds to microtubular protein tubulin in dimeric form
- Drug-tubulin complex adds to forming end of microtubules to terminate assembly
- Polymerisation of microtubules occurs, Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interface with chromosome segregation, M phase
Podophyllotoxins
Blocks cells in late S-G2 phase of cell cycle via topoisomerase II inhibition
DNA damage through strand breakage induced by formation of tenary complex of drug, DNA, and enxyme
Etoposide : lung cancer, testicular cancer, lymphoma
Teniposide : ALL
Toxicities : Myelosuppression, Mucositis, GI toxicity
Camptothecins
Interfere with Topoisomerase I activity
- DNA damage
1. S phase specific
2.Topotecan: Ovarian and cervical cancers.
3.Irinotecan: Colorectal cancer in combination with 5-FU.
- prodrug that metabolises to active inhibitor SN-38
4.Major Toxicities: Diarrhea, Myelosuppression.
Taxanes
- Alkaloid esters derived from Yew plant (Paclitaxel/Docetaxel).
- MOA: Interferes with the normal function of microtubule breakdown and as result hyperstabilize microtubule structure.
- Specifically binds to β subunit of tubulin.
- The resulting microtubule/paclitaxel complex does not have the ability to disassemble.
- This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their functions as a mechanism to transport other cellular components.
- In contrast to the taxanes, the vinca alkaloids interfere with assembly of spindle proteins during mitosis.
- Both, taxanes and vinca alkaloids are therefore named spindle poisons or mitosis poisons, but they act in different ways.
- Both used for treatment of lung, ovarian, breast and head and neck cancers.
- Major side effects: Myelosuppression, alopecia, neuropathy, allergies.
Folate
Folate
Essential dietary factor from which THF cofactors are formed to provide single carbon groups for the precursors of DNA and RNA
Must be reduced by DHFR to THF to function as folate cofactor
MTX is a folic acid analogue that competitively inhibits dihydrofolate reducatse (DHFR), an enzyme that catalyzes the formation of tetrahydrofolate (THF) from dihyrdofolate (DHF).
DHFR is primary site of action
MTX prevents formation of THF, causing intracellular deficiency of folatecoenzymes and accumulation of toxic inhibitory substrate DHF polyglutamate
One Carbon Transfer reactions for purine and thymidylate synthase cease
ALL, meningeal leukemia, osteoscarcoma, Burkitts’s and non-hodgekin’s lymphoma, BC, ovary, bladder cancer
Side effects : bone marrow suppression, need to rescue with leucovorin(folinic acid); nephrotoxic, give sodium bicarbonate to alkalinise urine
Purine Antagonists
Purine Antagonists
Mercaptopurine
Must be metabolised by HGPRT to nucleotide form, which inhibits numerous enzymes of purine nucleotide interconversion
1. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme in purine metabolism.
2. 6-mercaptopurine must be converted to the nucleotide 6-mercaptopurine ribose phosphate by
HGPRT. 6-mercaptopurine can also be converted to 6-methylmercaptopurine ribonucleotide.
3. 6-mercaptopurine ribose phosphate and the methylated nucleotide are cytotoxic because they inhibit de novo purine biosynthesis.
4. Both block the amidotransferase that is responsible for the first step in purine biosynthesis, namely the formation of 5-phosphoribosylamine by feedback mechanism.
5. Used for the treatment of leukemia (AML/CML).
6. Major side effects include myelosuppression, N/V, diarrhoea.
Pyrimidine Antagonists
Pyrimidine Antagonists
- 5-FU inhibits Thymidylate Synthase to cause depletion of thymidylate
- 5-FU incorporated into DNA and inhibits RNA processing
1. Like the purine anti metabolites, 5-fluorouracil must be metabolically activated to a nucleotide, in this case 5-fluoro-2’-deoxyuridine-5’-monophosphate (FdUMP).
2. The cytotoxicity of 5-fluorouracil is due primarily to inhibition of DNA synthesis caused by a FdUMP-produced blockage of thymidylate synthase.
3. Thymidylate synthase normally transfers a methylene group from reduced folic acid to deoxyuridylate monophosphate to form thymidylate, which is essential for DNA synthesis.
4. Cytotoxicity, may also be due to incorporation of 5’-fluorouridine triphosphate into RNA, which leads to fraudulent RNA formation.
Uses : ovary, bladder, prostate, pancreatic cancer, BC, GI cancer
Major Toxicities: myelosuppression, mucositis, dermatitis, diarrhea and cardiac toxicity.
