Drugs that Prevent DNA Synthesis

Question 1

By mechanism, what are the two types of drugs that prevent DNA synthesis?

Answer 1

1. nucleotide synthesis inhibitors

2. inhibitors of DNA synthesizing enzymes

Question 2

What are the three sets of structural analogs that prevent DNA synthesis?

Answer 2

1. folic acid analogues
2. pyrimidine analogues
3. purine analogues

Question 3

For the folate analogues, how do some cancer cells have selective toxicity? Primary resistance?

Answer 3

those have overexpress the folate receptor will have selective toxicity
those that underexpress the reduced folate carrier will have primary resistance

Question 4

What does methotrexate inhibit?

Answer 4

competitive inhibitor of DHFR

Question 5

What are the toxic effects of the folate analogues?

Answer 5

1. primarily toxic effects on bone marrow and GI epithelium
2. pneumonitis
3. hepatic fibrosis
4. alopecia, dermatitis
5. MTX is an abortifacaent

Question 6

What drug is administered after high dose methotrexate as a “folate rescue”. Why does it work?

Answer 6

leucovorin - a reduced form of folinic acid
it works because the high dose MTX forces the cell to take it up via the folate receptor. then leucovorin enters the cell via the RFC, which is mutated in the cancer cells. So the normal cells get the folate they need, but cancer cells don’t

Question 7

What adminstration route can you NOT use for leucovorin?

Answer 7

intrathecal - you’ll die

Question 8

What are the two pyrimidine analogues we know?

Answer 8

5-fluorouracil

capecetabine

Question 9

What’s the mechanism of action for the pyrimidine analogues? AKA, wat enzyme do they inhibit? h

Answer 9

they decrease biosynthesis of pyrimidine nucleotides by inhibitin thymidulate synthase, which is the rate limiting step in DNA synthesis - so you get a “thymineless death” of rapidly growing cells

Question 10

How does resistance generally develop against the pyrimidine analogues?

Answer 10

increased expression of thymidylate synthase

decreased activiation of prodrugs by decreased pyrimidine monphosphate kinase activity

Question 11

Although pyrimidine analogues can enter the pyrimidine synthesis pathway at 3 different places, which is the key entry point?

Answer 11

the conversion of UMP to UDP which is catalyzed by pyrimidine monophosphate kinase

Question 12

Why must 5-FU be given IV?

Answer 12

Because it has limited oral bioavailability because gut mucos has high concentrations of diydropyrimidine dehydrogenase

Question 13

Significant metabolic degradation ocurs for 5-FU. How is it eliminated?

Answer 13

80% hepatic

20% rena;

Question 14

Inherited deficiency of what will lead to a greatly increased drug sensitivity?

Answer 14

dihydropyrimidine dehydrogenase - because it doesn’t get degraded

Question 15

How is capecitabine related to 5-FU?

Answer 15

Capecitabine is converted to 5-FU thorugh a 3 step process

Question 16

Why does capecitabine have higher selective toxicity than 5-FU?

Answer 16

Because the last step in the conversion of capecitabine to 5-FU is though thymidine phosphorylase, which is overexpressed in many tumours

Question 17

5-FU and capecitabine tend not to be particularly effective when given alone, so what are they combined with?

Answer 17

methotrexate

Question 18

Does 5-FU have a relatively high or low therapeutic index?

Answer 18

low - even for an antineoplastic

Question 19

What are the primary toxic effects of 5-FU?Which one is specific to 5-FU?

Answer 19

Primary effects are on bone marrow (myelosuppression reaches mas at 9-14 days) and GI epithelium

Also alopecia, dermatitis and hand-foot syndrome

the specific one is acute cerebellar syndrome

Question 20

What are the two purine analogs we learned?

Answer 20

6-mercaptopurine and 6-thioguanine

Question 21

Where to 6-MP and 6-TG enter the salvage pathway? AKA…which enzyme activates them?

Answer 21

Where PRPP reacts with hypoxanthine or guanine bases to form IMP or GMP respectively - catalyzed by HGPRT

Question 22

What enzyme is then inhibited by 6-MP and 6-TG?

Answer 22

guanylyl kinase (which converts GMP to GDP)

Question 23

As the IMP and GMP buildup because of the block on guanylyl kinase, what three enzymes experience “pseudofeedback inhibition?”

Answer 23

the enzymes earlier on in the pathway: PRPP synthetase (PRPS), guanylyl amidotransferase (GPAT), and HGPRT

Question 24

Azathioprine is converted to 6-mercaptopurine, but what is it used for primarily?

Answer 24

immunosuppression, no antineoplastic

Question 25

What are the two metabolic pathways in the liver for 6-mercaptopurine?

Answer 25

1. xanthine oxidase oxidizes it to an inactive form

2. methylatin and subsequent oxidation

Question 26

Why is allopurinol often given during chemotherapy of hematologic cancers?

Answer 26

To prevent hyperuricemia due to tumor cell lysis

Question 27

What is tumor lysis syndrome?

Answer 27

It’s caused by the sudden rapid deaht of millions of cells - leads to development of electrolyte and metabolic disturbances that can produce life-threatening complications like hyperuricemia

Question 28

Specifically, what is prevented by the co-administration of allopurinol?

Answer 28

it prevents the nephrotoxicity and acute gout that would be produced by the excessive uric acid

Question 29

Which purine analog can you give with allopurinol and which one do you have to be really careful with?

Answer 29

6-TG is gine, but you have to be careuful with 6-MT because it is metabolized by xanthine oxidase, which is inhibited by allopurinol

you have to reduce the 6-MP dose to 25% of normal

Question 30

What are the 4 antimetabolites that inhibit DNA synthesizing enzymes? WHat’st he 5th that’s not an antimetabolite?

Answer 30

cladarabine, cytarabine, fludaraine, gemcitabine…hydroxyurea