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
What adverse-effect is unique to Bleomycin?
Pulmonary toxicity
What adverse-effect is unique to Mitoxantrone?
Blue discoloration of nails, sclera and urine
What is seen in the acute form of Doxorubicin induced cardiotoxicity?
What is seen in the chronic form?
Acute: occurs within the first 2-3 days. Presents with arrhythmias, pericarditis, myocarditis. It is often transient and asymptomatic.
Chronic: dose-dependent and may lead to DCM-associated HF.
What is the MOA of tyrosine kinase and GF inhibitors?
What is the mechanism of resistance?
Inhibition of GF receptor signaling and inhibition of tyrosine kinase activity.
Point mutations in drug binding sites.
What adverse-effects are associated with tyrosine kinase and GF inhibitors?
N/V
Acneform skin rash and hypersensitivity
-Cetuximab
What does the tyrosine kinase inhibitor Imatinib inhibit specifically?
What is it the first line therapy for?
Inhibits the BCR-ABL oncoprotein.
AML - t(9;22) translocation.
What is the unique MOA of Ziv-aflibercept (GF inhibitor)?
It is a recombinant fusion protein made of portions of human VEGF-R (a soluble receptor for VEGF and PIGF). Binding of VEGF ligands prevents their interactions with VEGF-R.
It inhibits VEGF-R signaling overall.
What are the PD-1 (T-cell) inhibitors? (2)
What is the class MOA?
What cancers are they used to treat? (3)
Nivolumab, Pembrolizumab.
Immune checkpoint inhibitors.
Melanoma, non-small cell lung cancer, Hodgkin’s lymphoma.
What are the PD-L1 (T-cell) inhibitors? (3)
What is the class MOA?
What cancers are they used to treat? (3)
Atezolizumab, Avelumab, Durvalumab.
Immune checkpoint inhibitors.
Bladder cancer, non-small cell lung cancer, Merkel cell skin cancer.
What are the adverse-effects of immune checkpoint inhibitors (2 categories)?
Fatigue, nausea, loss of appetite, itching
Immune system attack of normal organs.
What drug class do the following fall into?
Bis (chlorethyl) amines
Nitrosureas
Non-classic
Platinum analogs
Alkylating agents
MOA
- nib
- mab
- nib: TK inhibitor (BCR-ABL, PDGFR-B tyr kinase and c-kit)
- mab: GF-R inhibitor
What is a use of leucovorin in combination with MTX?
It helps protect healthy cells from damage due to MTX
What drug is associated with significant GI toxicity?
5-FU
Wat drug is associated with hand-foot syndrome?
Pemetrexed
What drug is a prodrug? What class is it in?
Dacarbazine; alkylating agent.
How can methotrexate-resistance develop?
Decreased drug transport.
Decreased formation of polyglutamate metabolites by FPGS.
How can -trexate-resistance occur?
Decreased formation of polyglutamate metabolites by FPGS.
Drug class: Cytyrabine
Antimetabolites
Drug class and MOA: Vinblastine, Vincristine, Vinorelbine
Natural product; tubulin disrupters.
Drug class and MOA: -taxels
Natural products; tubulin enhancers.
Drug class and MOA: -tecans
Natural products; topoisomerase-1 inhibitors.
Drug class and MOA: Etoposide
Natural products; topoisomerase-2 inhibitor.
A/E: Vincristine
Neurotoxicity
A/E: Paclitaxel, Docetaxel
Hypersensitivity reactions
A/E: Topotecan, Irnotecan
Diarrhea
Doxorubicin MOA:
MOR:
A/E:
Inhibition of topoisomerase-2, generation of free radicals and DNA intercalation.
Point mutations in topoisomerase-2.
Increased expression of efflux pumps.
Cardiotoxicity
Mitomycin MOA:
MOR:
Induction of DNA cross-linking.
Increased expression of efflux pumps.
Bleomycin MOA:
MOR:
A/E:
DNA fragmentation and single/double-stranded bond breaks due to free radical formations.
Increased expression of bleomycin hydrolase.
Pulmonary toxicity.
Cetuximab drug class:
A/E:
GF inhibitor.
Acne-like rash and hypersensitivity.
MOA and drug class: Nivolumab, Pemprolizumab
A/E:
immune checkpoint inhibitors; PD-1 inhibition.
Fatigue, nausea, loss of appetite and pruritis.
Immune system attack of other organs.
MOA and drug class: Atezolizumab, Avelumab, Durvalumab
A/E:
Immune checkpoint inhibitors; PD-L1 inhibition.
Fatigue, nausea, loss PF appetite and pruritis.
Immune system attack of other organs.
What is the MOR of immune checkpoint inhibitors?
T-cell function/production problems.
