Cancer Pharmacology 1 Flashcards
What is the role of oncogenes and tumor suppressor genes?
Oncogenes positively influence tumor development - i.e. Ras.
Tumor suppressors are genes that negatively impact tumor growth - i.e. p53.
What is neoadjuvant chemotherapy?
What is adjuvant chemotherapy?
The use of chemotherapy in patients prior to other treatment.
Additional chemotherapy given for a defined period of time after surgery. It helps prevent relapse.
What is primary/inherent chemotherapeutic resistance?
Drug resistance by the cancer cell in the absence of prior exposure.
“Genetic instability of cancer” - p53 mutations.
What is acquired chemotherapeutic drug resistance?
The development of resistance in response to exposure to a cancer drug.
Genetic change - amplification or suppression of a particular gene.
Where is p-glycoprotein (PGP, MDR1) expressed most?
What does a high baseline [PGP] suggest?
What overexpression cause?
Tissues with barrier functions - kidneys, liver, GI tract.
Pharmacological barrier sites - BBB, placenta.
Primary/inherent resistance to natural products.
Acquired drug resistance.
Which cell populations tend to be the most susceptible to adverse-effects of chemotherapy? (5)
Non-cancerous proliferating drugs.
- BM precursors of blood cells (cytopenias, myelosuppression)
- Intestinal epithelial cells
- Oral mucosa
- Gonadal cells
- Hair follicles (alopecia)
What is the MOA of alkylating agents?
Which cells are most vulnerable?
Transfer alkyl groups to DNA leading to DNA cross-linking. The causes an arrest in late G1/early S phase.
Replicating cell are most vulnerable.
What are 3 mechanisms of resistance to alkylating agents?
Increased capacity to repair DNA lesions by increasing the activity of DNA repair enzymes.
Decreased cellular transport of the alkylating drugs.
Increased activity of glutathione and glutathione-associated proteins (leads to inactivation).
What are the major side-effects of alkylating agents? (4)
Effects at rapidly growing tissue.
- BM suppression
- GI tract: diarrhea
N/V/D
Blistering at site of administartion.
Carcinogenic - increased risk of secondary malignancies (AML).
Which alkylating agent crosses the BBB?
Carmustine
What is the MOA of antimetabolites?
What cells are most susceptible?
They mimic and/or reduce the essential components needed for the formation of DNA, RNA and proteins.
Arrest and/or DNA damage occurs during S phase.
Replicating cells are most susceptible.
What are 3 mechanisms for resistance for antimetabolites?
Inhibition of metabolism into active metabolites.
Decreased drug transport.
Decreased polyglutamate metabolites by folyl polyglutamate synthase (FPGS) (important for MTX, pemetrexed, pralatrexate).
What adverse-effects are associated with antimetabolites? (3)
Myelosuppression
N/V/D
Hand-foot syndrome: painful erythema and swelling of hands and feet.
What are the unique MOA for Cytarabine (antimetabolic)? (3)
It is converted to ara-CTP. Ara-CTP competitively inhibits DNA pol-a and DNA pol-B.
Ara-CTP is incorporated into DNA.
Ara-CTP is incorporated into RNA.
What is the unique MOA of 6-mercaptopurine?
It is a purine antagonist. It is metabolized by HGPRT to form 6-thioinosinic acid, which inhibits de novo purine synthesis.
The triphosphate form can be incorporated into RNA or DNA.
What are the 2 general categories of natural products?
Tubulin polymerization: disruptive and enhancing.
Topoisomerase inhibitors (1 and 2)
What are the 3 drugs that disrupt tubulin polymerization?
What are the 3 drugs that enhance tubulin polymerization?
Disrupt: Vinblastine, Vincristine, Vinorelbine.
Enhance: Paclitaxel, Docetaxel, Cabazitaxel.
What are the 2 topoisomerase 1 inhibitors?
What is the only topoisomaerse 2 inhibitor?
Topoisomerase 1: Topotecan, Irinotecan.
Topoisomerse 2: Etoposide.
What are the 2 mechanisms for resistance of natural products?
P-glycoprotein mediated drug efflux.
Point mutations in drug binding pockets (i.e. topoisomerase inhibitors).
What are the adverse-effects of natural products? (5)
Myelosuppression
N/V
Neurotoxicity - Vincristine
Hypersensitivity - Paclitaxel, Docetaxel
Diarrhea - Topotecan, Irinotecan
What is the one natural product that has a way around resistance due to PGP?
Cabazitaxel
What are 3 MOAs associated with antitumor antibiotics and which drug falls into each one?
Inhibition of topoisomerase 2, generation of free radicals (DNA damage), DNA intercalation.
-Anthracyclines (Doxorubicin)
Induction of DNA cross-links.
-Mitomycin
DNA fragmentation and single/double strand breaks due to free radical formation.
-Bleomycin
What are 3 mechanisms of resistance to antitumor antibiotics and which mechanisms effect which drugs?
Point mutations in topoisomerase 2, suppression of apoptotic signaling.
-Doxorubicin
Increased expression of multidrug resistant efflux pumps.
-Doxorubicin, Mitomycin
Upregulation of bleomycin hydrolase enzyme.
What are common adverse-effects of antitumor antibiotics?
Myelosuppression
N/V
Free radical-mediated cardiotoxicity
-Doxorubicin
Blue discoloration of nails, sclera and urine
-Mitoxantrone
Pulmonary toxicity
-Bleomycin
