Pharm. of Antineoplastic Agents

Question 1

Name the tumor determinants

Answer 1

1) Growth Fraction
2) Mass Doubling Time
3) Tumor Burden

Question 2

What 3 tissues are most affected and what are the SE?

Answer 2

1) Fair Follicles- alpecia
2) GI tract- Nausea & Vomiting
3) Bone Marrow- myelosuppression

Question 3

Does an increase in Growth Fraction increase or decrease Doubling Time?

Answer 3

Decrease

Question 4

Would a slow doubling time respond better or worse to Tx?

Answer 4

worse

Question 5

what type of tumors (tumor burden) do not respond well to drug therapy

Answer 5

larger, bulky tumors

Question 6

describe a log cell-kill

Answer 6

a given drug regimen will eliminate a constant proportion of cells, not a constant number of cells (most solid tumors do NOT exhibit exponential growth)

Question 7

Describe Vinblastine

Answer 7

binds to tubulin->inhibition of mitosis->metaphase arrest, cells accumulate in G-2 and S phases. Then add ARA-C which blocks DNA synthesis that occurs in the S phase

Question 8

Describe Mechlorethamine

Answer 8

a Alkylating agent (nitrogen mustard), forms highly reactive intermediates; 2-choloroethyl side chain cyclizes via a 1st order SN1 rxn forming highly reactive ethyl eniminium ion which in turn forms a carbonium ion or other reactive intermediate. When the reactive species reacts with DNA or protein, the alkyl gorup is transferred->Covalent bond (on DNA the most susceptible site is the #7 nitrogen of guanine which is highly neutrophilic.

Question 9

What are the consequences of Alkylation?

Answer 9

1) Ring Opening
2) Depurinization
3) Miscoding
4) Cross-linking

Question 10

What is a major SE of Mechlorethamine?

Answer 10

powerful vesicant, so avoid extravasation otherwise serious blisters will occur, can Tx with Na Thiosulfate

Question 11

What is Aldophosphamide (from Cyclophosphamide) metabolized to?

Answer 11

Carboxyphophamide, Phosphoramide mustard, Acrolein

Question 12

What is Phosphoramide mustard further metabolized to?

Answer 12

nornitrogen mustard (an alkylating agent)

Question 13

What is the major SE of Acrolein?

Answer 13

Hemorrhagic Cystitis

Question 14

What are the the 2 Nitrogen Mustards?

Answer 14

Mechlorethamine and Cyclophasphamide

Question 15

What are the major SE of Nitrogen Mustards?

Answer 15

1) Leukopenia
2) Hemorrhagic Cystitis
3) SIADH
4) Misc.

Question 16

What is Filgrastim used for?

Answer 16

counter SE of leukopenia from Nitrogen Mustards: counter marrow suppression by acting like G-CSF and producing monocytes, fibroblasts, and endothelial cells by stimulating proliferation and differentiation of neutrophil progenitors

Question 17

What does Sargramostim do?

Answer 17

counter SE of leukopenia from Nitrogen Mustards: a GM-CSF used to accelerate myeloid recovery after chemotherapy or BMT, multilineage in that it activates granulocytes, macrophages, megakaryocytes and erythrocytes

Question 18

How do you avoid Hemorrhagic Cystitis?

Answer 18

a) well hydrating

b) MESNA (mercaptoethanesulfonate Na) reacts with the DB of Acrolein

Question 19

What is SIADH?

Answer 19

syndrome of inappropriate ADH; water intoxication, can cause hypoatremia(low Na) and seizures; Tx with loop diuretic furosemide (Lasix)

Question 20

Describe Nitrosoureas

Answer 20

main differences from mustards is that, in addition to alkylating DNA, they do carbamoylate proteins, preferred site of attack is the oxygen on the #6 carbon, not the #7 nitrogen of guanine

Question 21

Describe the MOA of Nitrosoureas

Answer 21

like mustards, are not phase spedific but their effects are seen during the S phase. They are very lipophilic and readily cross the BBB; Nitrosoureas are NOT vesicants

Question 22

What are the Folic Acid Analogs?

Answer 22

Methotrexate(MTX) and Pralatrexate

Question 23

what is the importance of N5-N10-methylenetetrahydrofolate(FH4) in Folic Acid Analogs

Answer 23

donates a 1-carbon unit in the form of -CH3 to deoxyuridine monophosphate(dUMP) in the synthesis of thymidine (aka 5-METHYL-uacil)

Question 24

describe high and low dose MTX

Answer 24

given as high dose followed by leucovorin rescue; low doses of leucovorin are given to selectively “rescue” healthy cells

Question 25

why are tumor cells not rescued

Answer 25

1) b/c leucovorin is given in low doses

2) tumor cells have impaired folate uptake

Question 26

What are the cytotoxic effects of MTX

Answer 26

apparent in the S phase

Question 27

What toxic effects should you look for in folic acid analogs

Answer 27

an early sign of toxicity is mucositis. Severe toxicity causes diarrhea

Question 28

Describe the Pyrimidine Analogs

Answer 28

Cytarabine (aka ARA-C) the 2 important differences from deoxycytidine:

1) it contains an arabinose sugar instead of ribose
2) the 2’-OH group is trans to the 3’-OH group whereas with deoxycytidine they are cis

Question 29

Describe the mechanisms of Pyrimidine Analogs

Answer 29

1) steric hindrance- improper stacking of bps causing fragmentation
2) inhibition of elongation, when it incorporates at the terminal position

Question 30

what is DepoCyt

Answer 30

liposomal preparation of Cytarabine

Question 31

Describe 6-Mercaptopurine (6-MP)

Answer 31

a Purine Analog, has an S in lace of O on the #6 carbon that facilitate uptake by cells, and is a substrate for hypoxanthamine guanine phosphoribosyl transferase