Lecture 4 Anticancer drugs
Log Cell Kill
10^10 cancer cells present in body. We are killing 99.9% of all cancer cells. This seems amazing but lets see what it means. 10^10-10^7 which is still over a million cells. They will regrow so lets do it again. So now its 10^8- 10-^5. The point is that chemotherapy needs to be continued for an extended period of time. There are several implications here. 1. if the therapy works and kills the tumors there will be diminishing return. We need to continue bc there will be a small amount of cells. 2. Treatments need to be spaced out to allow normal tissue regrowth. (recoop) We cannot give too much time between cycles, fine balance.
5. Which of the following drugs is an S-Phase-specific anti cancer agent that interferes with nucleotide biosynthesis? a) Prednisone b) Cyclosporine c) Cyclophosphamide d) Methotrexate 6.Which of the following anticancer drugs is an alkylating agent that might cause secondary malignancies? a) 5-Fluorouracil b) Cyclophosphamide c) Paclitaxel (Taxol) d) Methotrexate 7. Myelosuppression (bone marrow inhibition) in response to chemotherapy lasts approximately how long? [hint: about twice the time that it takes to reach the minimum white blood cell count] a) 2 days b) 22 days c) 64 days d) 100 days
5. Which of the following drugs is an S-Phase-specific anti cancer agent that interferes with nucleotide biosynthesis? d) methotrexate 6.Which of the following anticancer drugs is an alkylating. agent. that might cause secondary malignancies? b) cyclophosphamide 7. Myelosuppression (bone marrow inhibition) in response to chemotherapy lasts approximatly how long? [hint: about twice the time that it takes to reach the minimum white blood cell count] b) 22 days
Combination Chemotherapy: Goldie-Coldman Hypothesis What are the 3 criteria used for the selection of these drugs? 1. 2. 3.
Cancer is a genetic disease. More proliferations is related to the drug resistance. High rate of mutations causes resistance. If we apply 2 chemotherapies at the same time, it is less likely to acquire a mutation. Main idea: decrease probability of resistance and probability of cancer reoccurrence. Non-overallping toxicities between multiple cancer drugs.
Methotrexate (masquerades)
Class: Anti-cancer (S-phase)/immunopharm prolif inhibititor Target/mechanism: inhibits dihydrofolate reductase (DHFR) Spectrum: Antimetabolite (folate mimic)- kills dividing cells Adverse affects: Mucositis
5-Fluorouracil
Class: Anti-cancer (not phase specific) Target/mechanism: Thymidylate synthetase inhibitor (folate synthesis inhibitor) Spectrum: Antimetabolite Adverse affects: Myelosuppresion/mucositis
Cyclophsosphamide
Class: Anti-cancer (not phase specific)/immunopharm proliferative inhibition Target/mechanism: DNA crosslinking (alkylating) Spectrum: antimetabolite (kills dividing cells) Adverse effects: Myelosuppresion/secondary malignancy/hemorrhagic cystitis
Imatinib
Class: Anticancer (not phase specific) Target/mechanism: Inhibits tyrosine kinase Spectrum: Chronic leukemia CML
Cytosine Arabinoside
Class: anti-cancer (S-phase) Target/mechanism: inhibits DNA elongation Spectrum: Antimetabolite Adverse affects: Myelosuppression
Cisplatin
Class: anti-cancer (not phase specific) Target/mechanism: DNA cross-linking Adverse effects: renal (cumulative) - major dose-limiting toxicities, peripheral neuropathy/causes minimal myelosuppression
Doxorubicin and Etoposide
Class: anti-cancer (not phase specific) Target/mechanism: Topo 2 inhibitor Adverse affects: myelosuppression, cardiotoxicity (dose-related/cumulative)
Tumor Growth Slide When are tumors most chemo-sensitive? What happens to the growth fraction when the tumor is too large? How is growth fraction affected by tumor size?
Growth fraction = amount of cells growing in a tumor. Larger the tumor, the slower it grows and the growth fraction decreases, efficacy of cytotoxic drugs will be lower In tiny tumors where growth fraction is higher, cytotoxic chemotherapy will be most affective with smaller tumors. Clinically undetectable. Remove large tumors with sx, then use chemotherapy to get rid of tiny tumors that are undetectable. Mops them up. 10^9 Number of cells. Begins to slow down. Highest growth of tumor is before it is clinically detectable.
Explain the differences between Log-kill hypothesis, norton-simon hypothesis, and dose-density. What does the Goldie-Coldman hypothesis say?
Tumors don't grow logarithmically
Explain the difference between phase-specific and phase-non-specific anticancer drugs
phase-nonspecific: all phases of cell cycle cyclophosphamide (alkylating agent) cysplatin (cross-linkers) doxorubicin (topoisomerase inhibitor) Phase-specific: only on cells that are in specific phases Paclitaxel (microtubule drugs) Vincristine (microtubule drugs)
Difference between Intrinsic and Acquired Drug resistance
Initially sensitive and then over time becomes more resistance after chemotherapy.
Vincristine and Paclitaxel
Phase Specific Class: anti-cancer (Mitosis) Target/mechanism: binds to tubulin, blocks mitosis Adverse affects: neurotoxicity and myelosuppression - paclitaxel (minimal myelosuppression with vincristine)
