Antineoplastic Agents I

Front 1

Anti-neoplastics:
Non-specific: Alkylating Agents  Antibiotics  Anti-metabolites  Plant Alkaloids

Back 1

Side effects of alkylating agents:
Bone marrow suppression (dose limiting), GI toxicity, Hair loss (Alopecia), nausea, vomiting, gonadal dysfunction, infertility, All AA are mutagenic & carcinogenic

Front 2

1. Group of chemo agents that works by cross-linking DNA, covalent binding of alkyl groups onto macro-molecules: DNA, RNA, proteins
2. 1 can be monofunctional vs difunctional, what is the difference?
3. What are the 2 big classes of alkylating agents?

Back 2

1. Alkylating agents
2. One reactive group vs 2 reactive groups
3. Nitrogen mustards (MCC - Mechlorethamine, cyclophosphamide, Chlorambucil) & Nitrsoureas (CS - Carmustine, Streptozocin)

Front 3

Mechanisms of Tolerance to alkylating agents
Increased DNA repair, Increased Detoxification, Decreased apoptosis

Back 3

Extravasation injury - agent is active when it goes into the body, so if leaks into tissue while being injected (IV) will cause serious necrosis

Front 4

Mechlorethamine, Carmustine, Streptozocin, Cyclophosphamide, Chlorambucil
1. Drug that is a potent bifunctional alkylator, analogue of mustard gas, rapidly metabolized, no bioactivation needed, Risk of extravasation injury, used for Hodgkin's lymphoma

Back 4

1. Mechlorethamine

Front 5

Mechlorethamine, Carmustine, Streptozocin, Cyclophosphamide, Chlorambucil
1. Nitrogen mustard, Requires bio-activation by liver p450, causes bladder & renal toxicity due to ACROLEIN formation
2. What drug not listed above is often given with 1 to prevent ACROLEIN bladder toxicity, also increasing fluid intake helps

Back 5

1. Cyclophosphamide
2. Mesna

Front 6

Mechlorethamine, Carmustine, Streptozocin, Cyclophosphamide, Chlorambucil
1. Separate into nitrosurea & nitrogen mustard
2. Which is more lipid soluble so better at CNS penetration and brain tumors?

Back 6

1. Mechlorethamine, cyclosphosphamide, Chlorambucil --> Nitrogen mustards XXX Carmustine & Streptozoxin are Nitrosureas
2. Nitrosureas

Front 7

Mechlorethamine, Carmustine, Streptozocin, Cyclophosphamide, Chlorambucil
1. Drug that has good CNS penetration, orally available, prolonged cumulative myelosuppresion, used in the CNS
2. Drug that accumulates in liver, kidney and pancreas gets into cells by glucose transporter 2 GLUT 2 (on liver, small int., kidney & pancreas cells, can destroy pancreatic beta cells. Used in ENDOCRINE PANCREATIC cancer

Back 7

1. Carmustine
2. Streptozocin

Front 8

Carmustine, Cisplatin, Oxaliplatin, Streptozocin, Carbopatin
1. Widely used drug, dose limited due to renal toxicity, causes neurotoxicity (esp hearing loss), usu works even w/ drug resistance

Back 8

1. Cisplatin- minor myelosuppression so often used in combo drugs

Front 9

Antineoplastic antibiotics work by:
DNA intercalation, single-strand breaks, Topo II inhibition, generally cell cycle non specific
1. type that is more selective for S/G2?
2. Main mech. of resistance in this class?

Back 9

1. Anthracyclines - Doxo/Dauno-rubicin
2. Efflux through p-glycoprotein

also through: Decreased affinity for Topoisomerase II, Increased expression of Topoisomerase II, Increased DNA repair, Increased GST detoxification

Front 10

Cisplatin,"", Actinomycin D, Carmustine, bleomycin, Chlorambucil, Mitomycin, Anthracyclines
1. Drug that intercalates DNA, disrupts DNA/RNA synth., inhibits Topoisomerase II (unique side effect?)
2. Requires bioactivation in the liver, cross-links DNA & generates radicals. SE: cumulative myelosuppression, kidney damage, lung fibrosis

Back 10

1. Actinomycin - long half life (increases radiation sensitivity) - also myelosuppression & extravasation injury
2. Mitomycin

Front 11

Cisplatin,"", Actinomycin D, Carmustine, bleomycin, Chlorambucil, Mitomycin, Anthracyclines
1. DNA intercalator, causes DNA strand breaks, forms free radicals. SE, Hypersensitiviity, skin hyperpigmentation (50%), pulmonary fibrosis - dose limiting..... MILD MYELOSUPPRESION, used in testicular cancer

Back 11

1. Bleomycin

Front 12

Cisplatin,"", Actinomycin D, Carmustine, bleomycin, Chlorambucil, Mitomycin, Doxorubicin/ Daunorubicin
1. Works by topoisomerase II/helicase inhibition, interacalation of DNA, formation of free radicals.. SE: dose limiting myelosuppression, severe cardiac toxicity, cumulative life-time dose limit, extravasation injury

Back 12

Doxorubicin

Front 13

1. Fxn of topoisomerase II?

Back 13

1. Helps unwind and separate double stranded DNA

Front 14

Cisplatin,"", Actinomycin D, Methotrexate, Carmustine, bleomycin, Chlorambucil, fluorouracil & -tabine, Mitomycin, Anthracyclines, Mercaptopurine
1. Is a folic acid analog
2. Is a purine analog
3. Is a pyrimidine analog

Back 14

1. Methotrexate
2. Mercaptopurine
2. 5-gluoruracil, Capecitabine, gemcitabine

Front 15

1. Cell cycle phase that antimetabolites - methotrexate, mercaptopurine, fluorouracil) interfers w/ ?

-Actively transported into cells, begins activated in cells to be cytotoxic - inhibits target enzymes

Back 15

1. S- phase of DNA/RNA and protein

Front 16

Cisplatin, Actinomycin D, Methotrexate, Carmustine, bleomycin, Leucovorin, Chlorambucil, fluorouracil & -tabine, Mitomycin, Anthracyclines, Mercaptopurine
1. Drug that inhibits DHFR? SE: myelosuppresion (dose limiting, renal/liver toxicity)
2. Used to rescue normal cells from 1?

Back 16

1. Methotrexate
2. Leucovorin - folinic acid

Front 17

Cisplatin,"", Actinomycin D, Methotrexate, Carmustine, bleomycin, Leucovorin, Chlorambucil, fluorouracil & -tabine, Mitomycin, Anthracyclines, Mercaptopurine
1. MA: makes false nucleotides used in RNA/DNA synth. - INHIBITION OF THYMIDYLATE SYNTHASE : SE Dihydropyrimdine dehydrogenase deficiency DPD can lead to fatal OD
2. Why is Folinic acid given w/ 1?

Back 17

1. 5-fluorouracil - prodrug form - Capecitabine
2. Enhances the effect of the drug on thymidylate synthase inhibition

Front 18

Cisplatin,"", Actinomycin D, Methotrexate, Carmustine, bleomycin, Leucovorin, Chlorambucil, fluorouracil & -tabine, Mitomycin, Anthracyclines, Mercaptopurine
1. Converted by hypoxanthine guanine phospho-ribosyltransferase to nucleotides, inhibit de novo purine synthesis - used for leukemia. SE thiopurine-S-methyltransferase deficiency up toxicity, interacts w/ allpurinol

Back 18

1. Mercaptopurine

drug inhibits xanthine oxidase so decreases clearance if given w/ allopurinol

Front 19

1. 2 common resistance mech. to plant alkaloids?
Vinca alkaloids vs taxanes:
2. inhibits tubulin depolymerization
3. Inhibits tubulin polymerization

Back 19

1. Efflux pumps & mutation of target enzymes
2. Taxane
3. Vinca alkaloids
Tubulin - basic structural unit of microtubules, stabilize the cytoskeleton

Front 20

Cisplatin,Vinca Alkaloids, Chlorambucil, fluorouracil & -tabine, Taxane, Anthracyclines, Mercaptopurine
1. Binds tubulin & inhibits microtubule formation, depolymerization continues so Microtubule disintegrates, SE: extravasation injury, fatal when given intrathecal
2. CC stage blocked by 1?

Back 20

1. Vinca Alkaloids - Vincristine, Vinblastine
from the periwinkle plant
2. Blocks G2 & M

Resistance via increasing tubulin synthesis, efflux

Front 21

Cisplatin,Vincristine, Chlorambucil, fluorouracil & -tabine, Taxane, Vinblastine, Mercaptopurine
1. Vinca alkaloid, w/ neurotoxicity rate limiting, but low or no myelosuppression so often combo drug!
2. Vinca alkaloid, dose limiting myelosuppression, used in testicular cancer

Back 21

1. Vincristine
2. Vinblastine

Front 22

Cisplatin,Vinca Alkaloids, Chlorambucil, fluorouracil & -tabine, Taxane, Anthracyclines, Mercaptopurine
1. From the pacific yew tree, inhibits microtubule depolymerization - stabilizes microtubules. SE: hypersensitivity, peripheral neuropathy
2. Cell cycle stage it is active in

Back 22

1. Taxane = Paclitaxel / Docetaxel