Exam 3: Lecture 6, Medical Chemistry Cancer Drugs Part II

Question 1

Busulfan (Myleran) uses:

Answer 1

bone marrow transplantation

CML as conditioning drug

Question 2

Busulfan (Myleran) Toxicity

Answer 2

Pulmonary fibrosis, hyperpigmentation, lowered blood platelet count and activity

Question 3

Busulfan (Myleran) info

Answer 3

sulfuric acid ester with methane sulfuric acid acting as leaving group

1 or both methane ester can be displaced by N7 of guanine, meaning it can be bi-functional

admin oral/IV, neutral molecule with poor water solubility

Length of chain determines effect on DNA

Question 4

Thiotepa info

Answer 4

less reactive, used for more than 50 yrs

at acidic pH, aziriuine group protonated to provide a reactive aziridinium ion that alkylates DNA = active

Metabolic desulfurization leads to toxic metabolite (TEPA)

Admin IV, PO unreliable

Question 5

Thiotepa uses

Answer 5

Breast,ovarian, bladder cancer

Conditioning for Bone Marrow Transplant

Question 6

Thiotepa Toxicity

Answer 6

Myelosuppression, damage to hepatic and renal system

Question 7

Can TEPA alkylate DNA?

Answer 7

Yes, at N7 position of guanine typically

Question 8

Procarbazine (Matulane) info

Answer 8

alkylation of DNA by free radical intermediates

** In addition to methylation of O6 of guanine, C8/N7 can be alkylated**

Drug metabolized and activated in the liver

Question 9

O6 methylated guanine pair preferentially with….

Answer 9

Thymine, leading to point mutation resulting in cell destruction

Question 10

Procarbazine (Matulane) Uses

Answer 10

Hodgkins Lymphoma and certain brain cancers

Question 11

Procarbazine (Matulane) Side effects

Answer 11

inhibits enzymes involved in alcohol metabolism, disulfiram like effects

Question 12

Procarbazine (Matulane) MOA inhibited by….

Answer 12

drug-drug interactions with other sympathomimetic drugs, tricyclic antidepressants and tyramine

Question 13

Inhibition fo which enzyme causes Drug-drug interactions with Procarbazine?

Answer 13

CYP1A and CYP2B

Question 14

Dacarbazine (DTIC) MOA:

Answer 14

Methylates DNA guanine via diazomethane and/or Methyl Carbocation generated in situ

O6 and N7 positions of guanine most vulnerable to triazine methylation

Question 15

Dacarbazine (DTIC) bioactivated by…

Answer 15

CYP450

Question 16

Dacarbazine (DTIC) Uses:

Answer 16

Admin IV

Malignant Melanoma, Hodgkins Lymphoma

Question 17

Dacarbazine (DTIC) Toxicity:

Answer 17

Bone marrow suppression, Hepatotoxicity

Question 18

Temozolomide (Temodar)

Answer 18

Prodrug which nonezymatically gets covered to MTIC, which alkylates DNA

Admin orally, rapid absorption

Question 19

Temozolomide (Temodar) Uses

Answer 19

brain tumor

Question 20

Nitrosourea dual MOA:

Answer 20

alkylate DNA and carbamylate proteins

Question 21

Carmustine info

Answer 21

neutral molecule
highly lipophilic and poorly water soluble
Crosses BBB, used for several brain cancers

Question 22

Lomustine Info

Answer 22

similar structure, solubility and activity characteristics of BCNU

Question 23

Streptozocin info

Answer 23

composed of glycopyranose amino sugar and nitrosourea

Glycopyranose moeity imparts good water solubility = islet cell specificity

approved for treating metastatic cancer of pancreatic islet cells

Question 24

Nitrosourea activity results from….

Answer 24

non-enzymatic decomposition

Question 25

Carboplatin

Answer 25

less side effects than cisplatin

Question 26

Oxaliplatin

Answer 26

improved water solubility over cisplatin

Question 27

Cisplatin MOA:

Answer 27

acts by cross linking DNA (act as bifunctional ligands)

binding cisplatin affects both replication and transcription, and DNA repair. cant repair damage

**trans isomer well known to have faint cytotoxicity because its geometric structure allows less DNA adduct formation **

Question 28

Antimetabolites info

Answer 28

structurally related to naturally occurring compounds req for normal reactions but diff enough to mess with function of cells

used in cancer treatment, interfere with DNA production

work during S-phase

also effect RNA synthesis, most widely used due to efficiency

** false substrates, to look like a super attractive version of endogenous substrate so it gets bound **

Question 29

Folic Acid info

Answer 29

Essential dietary factor

converted by enzymatic reduction to tetrahydrofolate cofactors that provide C groups for synthesis of precursors of DNA and RNA

Question 30

DHFR can be inhibited by….

Answer 30

methotrexate

Question 31

Thymidylate synthase can be inhibited by….

Answer 31

5-Fluorouracil

Raltitrexed

Question 32

Rate limiting step in getting to dTMP

Answer 32

Thymidylate Synthase

Question 33

Without dTMP…

Answer 33

DNA will fragment and cell will die

Question 34

5-Fluorouracil info

Answer 34

Thymidylate synthase inhibitor

mainly used in treatment of colorectal cancer and pancreatic cancer

Question 35

5-Fluorouracil MOA:

Answer 35

transformed inside cell into cytotoxic metabolites that are incorporated into DNA/RNA.

S-Phase specific

Question 36

C6 position of dUMP is….

Answer 36

highly electrophilic due to being surrounded by N and O atoms

In 5-FU, electrophilicity is further increased due to strong EW F group

Question 37

Capecitabine

Answer 37

prodrug, enzymatically converted to 5-FU in tumor and phosphorylated by tumor-specific enzyme PyNPase

Oral admin, used in metastatic breast and colorectal cancers

Question 38

Methotrexate info

Answer 38

analog of vitamin folic acid

competitively inhibits action of DHFR enzyme on folic acid, indirectly inhibiting thymidine nucleotide production

Given Oral, IM and IV

Used in treatment of ALL, and recently some autoimmune diseases

Question 39

Rescue therapy for methotrexate

Answer 39

Leucovorin, converts to reduced folic acid dvts, has vitamin activity equivalent to folic acid

prevents lethal effects of methotrexate on normal cells

also inhibits active transport of methotrexate into cells