Hem & Onc - Pharm (Groups of Cancer Drugs) Flashcards
Pg. 401-405 in First Aid 2014 or Pg. 369-375 in First Aid 2013 Sections include: -Cancer drugs-cell cycle -Antineoplastics -Antimetabolites -Antitumor antibiotics -Alkylating agents -Microtubule inhibitors
What are the phases of the cell cycle and the major event occurring in each? Which cancer drugs act at each phase?
G1 - Synthesis of components needed for DNA synthesis = NO DRUGS ACT HERE; S - DNA Synthesis = ANTIMETABOLITES & ETOPOSIDE act here; G2 - Synthesis of components needed for mitosis = ETOPOSIDE & BLEOMYCIN act here; M - Mitosis = VINCA ALKALOIDS & TAXOLS act here (Note: G0 [rest] & Differentiation exit out of the cycle)
Which drug acts at multiple phases in the cell cycle? What are the phases in which it acts?
Etoposide; S & G2
What are the steps leading up to neoplastic cell division, starting at nucleotide synthesis and ending with cellular division? What are the important drugs that act at each step?
(1) Nucleotide synthesis - METHOTREXATE/5-FU & 6-MP (2) DNA - ALKYLATING AGENTS/CISPLATIN, DACTINOMYCIN/DOXORUBICIN, & ETOPOSIDE (3) RNA - NONE (4) Protein - NONE (5) Cellular Division - VINCA ALKALOIDS & PACLITAXEL
On what general process do methotrexate and 5-FU act? More specifically, what is their effect?
Nucleotide synthesis; Decrease thymidine synthesis
On what general process does 6-MP act? More specifically, what is its effect?
Nucleotide synthesis; Decrease purine synthesis
On what general process do Alkylating agents & Cisplatin act? More specifically, what is their effect?
DNA (Synthesis); Cross-link DNA
On what general process do Dactinomycin and Doxorubicin act? More specifically, what is their effect?
DNA (Synthesis); DNA intercalators
On what general process does Etoposide act? More specifically, what is its effect?
DNA (Synthesis); Inhibits topoisomerase II
On what general process do Vinca alkaloids act? More specifically, what is their effect?
Cellular division; Inhibit microtubule formation
On what general process does Paclitaxel act? More specifically, what is its effect?
Cellular division; Inhibits microtubule disassembly
What are 4 examples of antimetabolites? In what phase of the cell cycle do all of these cancer drugs act?
(1) Methotrexate (MTX) (2) 5-fluorouracil (5-FU) (3) Cytarabine (arabinofuranosyl cytidine) (4) Azathioprine/6-mercaptopurine (6-MP)/6-thioguanine (6-TG); S-phase
What is MTX? What is its mechanism?
Methotrexate; Folic acid analog that inhibits dihydrofolate reductase –> decreased dTMP –> decreased DNA and decreased Protein synthesis
What are the 4 cancers for which methotrexate is clinically used? What 5 other non-neoplastic clinical uses does methotrexate have?
CANCERS: (1) Leukemias (2) Lymphomas (3) Choriocarcinoma (4) Sarcomas; NON-NEOPLASTIC: (1) Abortion (2) Ectopic pregnancy (3) Rheumatoid arthritis (4) Psoriasis (5) IBD
What are the 4 toxicities/side effects associated with methotrexate?
(1) Myelosuppression (which is rversible with leucovorin [folinic acid] “rescue”) (2) Macrovesicular fatty change in liver (3) Mucositis (4) Teratogenic
What is 5-FU? What is its mechanism?
5-fluorouracil; Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex inhibits thymidylate synthase –> Decreased dTMP –> Decreased DNA & Decreased protein synthesis
What are the 3 cancers for which 5-FU is clinically used?
(1) Colon cancer (2) Pancreatic cancer (3) Basal cell carcinoma (topical)
What are the 2 toxicities/side effects associated with 5-FU?
(1) Myelosuppression (which is not reversible with leucovorin; instead, overdose rescue with uridine) (2) Photosensitivity
What is the major toxicity/side effect shared by both MTX and 5-FU? How is it handled in each case?
MYELOSUPPRESION; w/ MTX - reversible with leucovorin (folinic acid) “rescue… w/ 5-FU - not reversible with leucovorin, but instead overdose rescue with uridine
What is another name for Cytarabine? What is its mechanism?
Arabinofuranosyl cytidine; Pyrimidine anlog –> inhibition of DNA polymerase
What are the 2 cancers for which Cytarabine is clinically used?
(1) Leukemias (2) Lymphomas
What are the 3 toxicities/side effects associated with Cytarabine?
(1) Leukopenia (2) Thrombocytopenia (3) Megaloblastic anemia; Think: “CYTarabine causes panCYTopenia.”
What other drugs share the same mechanism as Azathioprine? What is this mechanism? What activates them to take this action?
6-Mercatopurine (6-MP) & 6-Thioguanine (6-TG); Purine (thiol) analogis –> Decrease de novo purine synthesis; HGPRT
What 3 conditions are prevented with use of Azathioprine?
Preventing organ rejection, RA, SLE (azathioprine)
Where are the 3 toxicities/side effects associated with Azathioprine, 6-MP, and 6-TG?
(1) Bone marrow (2) GI (3) Liver
Which drugs are metabolized by xanthine oxidase? Given this fact, what increases toxicity of this drug, and why?
Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have increased toxicity with allopurinol, which inhibits their metabolism
What are the antitumor antibiotics?
(1) Dactinomycin (actinomycin D) (2) Doxorubicin (Adriamycin, daunorubicin) (3) Bleomycin
What is the brand name for Dactinomycin? What is its mechanism?
Actinomycin D; Intercalates in DNA
For what 3 cancers is dactinomycin used clinically? In general, how is dactinomycin used clinically?
(1) Wilms’ tumor (2) Erwing’s sarcoma (3) Rhadomyosarcoma; Used for children tumors (Think: “children ACT out”)
What is/are the toxcity(-ies) associated with Dactinomycin?
Myelosuppression
What is the brand name for Doxorubicin? What is another drug that shares the same mechanism? What is their mechanism?
Adriamycin; Daunorubicin; Generate free radicals. Noncovalently intercate in DNA –> breaks in DNA –> Decreased replication
For what 3 cancers are doxorubicin/daunorubicin used clinically?
(1) Solid tumors (2) Leukemias (3) Lymphomas
What is/are the toxcity(-ies) associated with Doxorubicin/daunorubicin?
(1) Cardiotoxicity (dilated cardiomyopathy) (2) Myelosuppression (3) Alopecia (4) Toxic to tissues following extravasation
What is used to prevent cardiotoxicity as a result of doxorubicin/daunorubicin, and what kind of agent is this?
Dexrazoxane (iron chelating agent), used to prevent cardiotoxicity
What is the mechanism of bleomycin?
Induces free radical formation, which causes breaks in DNA strands
For what 2 cancers is bleomycin clinically used?
(1) Testicular cancer (2) Hodgkin’s lymphoma
What are 4 toxicities associated with Bleomycin? Which of these is minimal (relative to other antitumor drugs)?
(1) Pulmonary fibrosis (2) Skin changes (3) Mucositis. (4) Minimal myelosuppression
What are 3 examples of alkylating agents?
(1) Cyclophosphamide, ifosfamide (2) Nitrosoureas (carmustine, lomustine, semustine, streptozocin) (3) Busulfan
What other drug shares the same mechanism as cyclophosphamide? What is their mechanism? What is required for this action to occur?
Ifosfamide; Covalently X-link (interstrand) DNA at guanine N-7; Require bioactivation by liver
For what 4 cancers are cyclophosphamide and/or ifosfamide clinically used?
(1) Solid tumors (2) Leukemia (3) Lymphomas (4) Some brain cancers
What are 2 toxicities associated with cyclophosphamide and/or ifosfamide?
(1) Myelosuppression (2) Hemorrhagic cystitis (partially prevented with mesna [thiol group of mesna binds toxic metabolite])
What prevents hemorrhagic cystitis from cyclophosphamide/ifosfamide usage, and how?
Hemorrhagic cystitis, partially prevented with mesna (thiol group of mesna binds toxic metabolites)
What are 4 examples of Nitrosoureas? What is their mechanism? What is required for this action?
(1) Carmustine (2) Lomustine (3) Semustine (4) Streptozocin; Cross blood-brain barrier –> CNS; Cross-links DNA; Require bioactivation
For what cancers are Nitrosoureas used clinically?
Brain tumors (including glioblastoma multiforme)
What kind of toxicity and/or side effects are associated with Nitrosoureas?
CNS toxicity (convulsions, dizziness, ataxia)
What is the mechanism of Busulfan?
Cross-links DNA
What are 2 clinical uses for Busulfan?
(1) CML (2) Ablate patient’s bone marrow before bone marrow transplantation
What are 3 toxicities associated with Busulfan? Which of these occurs in almost all cases?
(1) Severe myelosuppression (in almost all cases) (2) Pulmonary fibrosis (3) Hypersegmentation
What are 2 examples of microtubule inhibitors?
(1) Vincristine, vinblastine (2) Paclitaxel, other taxols
What drug shares the same mechanism as vincristine? What is their mechanism and ultimate effect?
Vinblastine; Vinca alkaloids that bind to Beta-tubulin, inhibit its polymerization into microtubules, thereby preventing mitotic spindle formation (M-phase arrest)
For what 3 cancers are vincristine and/or vinblastine used clinically?
(1) Solid tumors (2) Leukemias (3) Lymphomas
What toxicities are associated with vincristine versus vinblastine?
VINCRISTINE - Neurotoxicity (areflexia, peripheral neuritis), paralytic ileus; VINBLASTINE - BLAsts bone marrow (suppression)
What is the mechanism and ultimate effect of Paclitaxel and other Taxols?
Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (i.e., anaphase cannot occur); Think: “it is TAXing to stay polymerized”
For what 2 cancers are Paclitaxel and/or other Taxols clinically used?
(1) Ovarian (2) Breast carcinomas
What 3 toxicities are associated with Paclitaxel and/or other Taxols?
(1) Myelosuppression (2) Alopecia (3) Hypersensitivity
What are 2 conditions treated by 6-MP? What other drug is used to treat these same conditions?
Leukemia, IBD (6-MP, 6-TG)
Draw a diagram showing the relationship between the following: (1) CH2-THF (2) DHF (3) DHF reductase (4) dTMP (5) dUMP (6) F-FU (7) MTX (8) THF (9) Thymidylate synthase.
See p. 403 in First Aid 2014 for diagram at bottom of page
