Antineoplastic Agents I

Question 1

Define Cancer

Answer 1

Group of many diseases of uncontrolled cellular proliferations, local tissue infiltration, and distant metasteses

Question 2

Carcinomas originate from

Answer 2

Ectodermal or endodermal tissues

Question 3

Sarcomas originate from

Answer 3

Mesodermal tissues (primarily connective tissue)

Question 4

Leukemia

Answer 4

Neoplasms that typically involve bone marrow and peripheral blood

Question 5

Lymphomas

Answer 5

Neoplastic proliferation of B or T cells that commonly present as masses within lymph nodes or other soft tissue

Question 6

Myelomas are diseases of what type of cell?

Answer 6

Plasma cell diseases

Question 7

What kind of genes are commonly mutated that promote constitutive cellular growth?

Answer 7

Proto-oncogenes

Question 8

Walk through tyrosine kinase receptor activation

Answer 8

1. Growth factor binds receptor
2. Tyrosine kinase activated
3. Activates Ras GTPase
4. Activated kinase cascade
5. MAP Kinase turns on genes in the nucleus that allows for proliferation

Question 9

3 common proto-oncogenes

Answer 9

EGFR oncogene
Ras oncogene
C-myc

Question 10

3 mechanisms of oncogene formation

Answer 10

Point mutation
Gene amplification
Chromosomal translocations

Question 11

3 checkpoints and what they’re checking

Answer 11

1. G2/M checkpoint- is DNA completely replicated
2. Metaphase/anaphase checkpoint- is DNA intact?
3. G1/S checkpoint- is environment appropriate for cell to divide

Question 12

What is the cell kill hypothesis?

Answer 12

Chemotherapeutic agents kill a constant proportion of cancer cells…not a constant number

Question 13

6 resistance mechanisms to drug therapy

Answer 13

1. Multidose resistance
2. EMT (epithelial-mesenchymal transition)
3. Drug efflux
4. DNA damage repair
5. Anti-metabolites not transported in
6. Rapid inactivation of anti-metabolitic drugs

Question 14

Cytotoxic methods of killing cancer cells

Answer 14

1. Perturbing normal DNA replication
2. Inhibiting topoisomerases
3. Perturbing mitosis
4. Starving cells of amino acids

Question 15

Targeted methods of killing cancer cells

Answer 15

1. Perturbing hormone and growth factor signaling
2. Inhibiting blood supply to tumor
3. Targeting activating proteins responsible for tumor growth

Question 16

Methotrexate MOA and ultimate goal

Answer 16

1. Prevents the ability of folate to be used in purine synthesis by inhibiting dihydrofolate reductase which, in turn, reduces synthesis of dTMP by inhibiting necessary cofactor for thymidylate synthetase
2. Reduces cellular proliferation and induces cellular death by preventing synthesis of RNA and DNA

Question 17

Methotrexate is useful as a single agent in treating

Answer 17

Acute Lymphoblastic Leukemia in children

Question 18

What drug is used to reduce methotrexate toxicity?

Answer 18

Leucovorin

Question 19

2 primary ways cancer can be resistant to methotrexate?

Answer 19

1. Altered forms of DHFR with decreased affinity for methotrexate
2. Elevated DHFR expression

Question 20

Methotrexate toxicities (5)

Answer 20

1. Bone marrow suppression
2. Intestinal epithelium death
3. Hepatic dysfunction
4. Interstitial pneumonitis
5. Nephrotoxicity

Question 21

5-Fluorouracil MOAs (2)

Answer 21

1. 5-FU is metabolized into F-fluorodexoyuridine monophosphate which inhibits thymidylate synthesis
2. FdUMP may be incorporated into RNA which eventually inhibits synthesis and function of RNA

Question 22

Most important antimetabolite to treat acute myelogenous leukemia (AML)?

Answer 22

Cytarabrine (ara-C)

Question 23

Ara-C MOA

Answer 23

1. Ara-C converted to ara-CMP by deoxycytidine kinase

2. Ara-CTP incorporated into DNA which inhibits DNA polymerase which halts DNA elongation

Question 24

Cytarabine is useless against ? and only active in which cell growth phase?

Answer 24

1. Ineffective against solid tumors

2. Only active in S-phase

Question 25

Cytarabine toxicity

Answer 25

1. Cerbellar syndrome (dysarthria, nystagmus, and ataxia)

Question 26

Cytarabine resistance (3)

Answer 26

1. Loss of deoxycytidine kinase
2. Reduced ability of tumor cells to transport ara-C
3. Cytidine deaminase upregulation

Question 27

Gemcitabine:
Activated by which enzyme?
MOA and inhibits which enzyme?

Answer 27

Activated by deoxycytidine kinase
Incorporated into DNA which inhibits synthesis and function
Inhibits ribonucleotide reductase

Question 28

Activation and MOA of 6-Thioguanine and 6-Mercaptopurine

Answer 28

6MP is activated to thio-IMP and 6TG is activated to thio-GMP by hypoxanthine-guanine phospho-ribosyltransferase (HGPRT)

Both inhibit purine synthesis and can be incorporated into DNA thus causing DNA damage

Question 29

Toxicity associated with 6TG and 6MP

Answer 29

Polymorphism in Thiopurine Methyltransferase causing reduced TPMT activity (which normally inhibits 6MP and 6TG) can cause toxicity

Question 30

Which enzyme activates Fludarabine?

MOA

Answer 30

Deoxycytidine kinase
Incorporated into DNA and RNA
Inhibits DNA Pol and RNR

Question 31

Standard therapy for Hairy Cell Leukemia

Answer 31

Cladribine

Question 32

Which enzyme activated Clardribine?

MOAs

Answer 32

Deoxycytidine kinase
Incorporated into DNA causing strand breaks
Inhibitor of RNR