Anticancer Drugs 2

Question 1

What is Azacitidine?

Answer 1

An injectable cytosine analog is incorporated into RNA and DNA, thus inhibiting protein synthesis and promoting apoptosis.

Question 2

Azacitidine is used primarily in the treatment of what?

Answer 2

Primarily in the treatment of myelodysplastic syndrome, a condition in which red cells, white cells and platelets do not mature successfully and crowd out healthy cells, rendering the patient susceptible to anemia, infection and bleeding problems.

Question 3

Methotrexate inhibits which enzymes?

Answer 3

primarily dihydrofolate reductase, but it also inhibits thymidylate synthase and two early enzymes (Glycinamide ribonucleotide transformylase (GARFT) and aminoimidazole carboxamide ribonucletide transformylase (AICARFT) in the purine biosynthetic pathways.

Question 4

Why are tetrahydrate cofactors vital for tumor growth?

Answer 4

they provide carbon groups for DNA (thymidylate and purines) and RNA (purines). Thus, replication is inhibited by blocking them.

Question 5

How is Methotrexate taken up into the cell? Effluxed?

Answer 5

Methotrexate is taken into the cell via folate uptake processes and can be effluxed by ABC transporters.

Question 6

How is Methotrexate trapped in a cell once it’s taken up via folate uptake processes?

Answer 6

the drug becomes polyglutamated. Both polyglutamated MTX and polyglutamated dihydrofolic acid retain the ability to inhibit enzyme targets.

Question 7

T or F. MTX causes few side effects at typical doses.

Answer 7

T.

Question 8

What side effects are caused by high doses of MTX?

Answer 8

At high doses, although used infrequently, fatal bone marrow toxicity can occur.

Question 9

How can the fatal bone marrow toxicity associated with high doses of MTX be avoided?

Answer 9

This toxicity can be prevented by early administration of leucovorin (oral or IV), and this therapy is termed leucovorin rescue.

Question 10

How does Leucovorin work?

Answer 10

Leucovorin is folinic acid; has activity that is equivalent to folic acid; and thus is readily converted to tetrahydrofolate.

Leucovorin, however, does not require dihydrofolate reductase for its conversion. Therefore, its function is unaffected by inhibition of this enzyme by drugs such as methotrexate. Leucovorin, therefore, allows for some purine and pyrimidine synthesis and can rescue normal cells from the effects of folate antagonists, like MTX.

Question 11

Outline the basic THF pathway.

Answer 11

pteridine + PABA converts to dihydropteridoic acid, converts to DFH using glutamate, converts to THF

Question 12

Which drug inhibits conversion of pteridine + PABA to dihydropteriodic acid?

Answer 12

sulfamethoxazole

Question 13

Which drugs inhibit conversion of DHF to THF (dihydrofolate reductase inhibitors)?

Answer 13

trimethoprim, methotrexate, and pyrimethamine

NOTE: The antimicrobial and antimalarial drugs have specificity for their respective targets and do not produce significant host toxicity such as might be produced by methotrexate.

Question 14

What is pyrimethamine commonly used to treat?

Answer 14

malaria

Question 15

What are some mechanisms of resistance to Methotrexate?

Answer 15

decreased uptake, increased efflux, decreased polyglutamation, increased DHFR levels and/or modified structure

Question 16

What are the side effects of Methotrexate?

Answer 16

In addition to myelosuppression, GI and pulmonary effects, primarily infiltrates and fibrosis and anemia in RA or psorasis

Question 17

How is Methotrexate eliminated?

Answer 17

urine, both by GF and RTS, especially in the first 12 hours after administration.

Question 18

Which drugs could inhibit the effects of Methotrexate?

Answer 18

For this reason, any drugs which interfere with renal excretion, for example the NSAIDs or probenecid (an inhibitor of RTS), can reduce methotrexate clearance and potentially increase drug associated toxicity.

Question 19

How does 5-flurouracil work?

Answer 19

a fluorinated pyrimidine which is converted in cells to:
1) 5FdUMP, this inhibits thymidylate synthase (TS) and leads to “thymineless death” of the cells,

2) FdUTP, to inhibit DNA synthesis, and
3) FUTP to interfere with mRNA translation

Question 20

Resistance to 5-FU?

Answer 20

decreased activation and mutation of TS

Question 21

What are some of the side effects of 5-FU?

Answer 21

hand-foot syndrome, acute chest pain, myelosuppression, anemia

Question 22

Hand and foot syndrome is also seen with administration of which drugs?

Answer 22

capecitabine and cytarabine

Question 23

What is hand-foot syndrome caused by?

Answer 23

occurs when anti-cancer drugs after the growth of skin cells and capillaries in the hands and feet. It escapes capillaries and causes tissue damage, with symptoms ranging from redness and swelling to blistering

Question 24

Leucovorin is also sometimes used with 5-FU. Why?

Answer 24

To “drive” intermediary metabolism into incorporating fluorouracil, thereby enhancing the activity of the drug against thymidylate synthase and the associated enzymes.

common in colorectal cancer treatment

Question 25

How is 5-FU administered?

Answer 25

IV only

Question 26

What is Capecitabine?

Answer 26

an oral pro-drug for fluorouracil, being metabolically converted to the active form intracellularly.

Question 27

Capecitabine is commonly used in treatment of what cancers?

Answer 27

metastatic breast and colorectal

Question 28

Does Capecitabine cause hand and foot syndrome also?

Answer 28

Yes, even more frequently than 5-FU.

Question 29

Is Cytarabine given orally?

Answer 29

NO, only IV, SC, or ITH- poor bioavailability

Question 30

What is Cytarabine? How does it work?

Answer 30

also known as cytosine Arabinoside or Ara-C is a pyrimidine anti-metabolite that requires activation intracellularly to Ara-CTP. Tumor cells are unable to remove Ara-CTP, inhibiting replication

Question 31

What are the mechanisms of resistance to Cytarabine?

Answer 31

decreased cellular uptake,

decreased activation of Ara-CTP from Ara-C

increased inactivation of ARA-C by conversion to an inactive metabolite, uracil arabinoside (Ara-U) via cytidine deaminase.

Question 32

What are some of the adverts effects of Cytarabine?

Answer 32

myesuppression, stomatitis, elevated hepatic enzymes, and noncardiogenic pulmonary edema with high dose, anemia

Question 33

What is Gemcitabine?

Answer 33

a deoxycytidine analog that is converted into the active diphosphate and triphosphate nucleotide forms intracellularly. Incorporation of gemcitabine triphosphate into DNA results in chain termination.

Question 34

Side effects of Gemcitabine?

Answer 34

In addition to myleosuppression, interstitial pneumonitis.

Question 35

Is Mercaptopurine a purine or pyridime antimetabolite?

Answer 35

purine. So is its cousin, thioguanine.

Question 36

Describe the 6-mercaptopurine pathway

Answer 36

6-mercaptopurine can be converted to 6-thiouric acid, 6-methyl mercaptopurine via TMPT, or 6-thionosine monophosphate via HGPRT

6- thionosine monophosphate, 6-thioxanthine monophosphate, 6-thioguanine monophosphate, which inhibits DNA purine synthesis

Question 37

How can conversion of 6-mercaptopurine to 6-thiouric acid be prevented?

Answer 37

allopurinol- leads to increased mercaptopurine toxicity and should be considered

Question 38

T. Genetic polymorphisms in the gene encoding TPMT may lead to three clinical TPMT activity phenotypes, i.e., high, intermediate, and low activity, which are associated with differing rates of inactivation of thiopurine drugs (mercaptopurine, thioguanine and azathioprine) and altered risks for toxicities.

Answer 38

T.

Question 39

Over 90% of the phenotypic TPMT variability across populations can be accounted for with just three point mutations that are defined by four non-functional alleles, i.e., ___, ___, ___, and ___.

Answer 39

TPMT*2, *3A, *3B, and *3C.

Can be manipulated in tailoring cancer therapy

Question 40

What are the mechanisms of resistance against Mercaptopurine?

Answer 40

decreased amount of HGPRT, Alternative mechanisms of resistance include enzyme mutation, and decreased drug uptake/increased efflux.

Question 41

What are the toxicities associated with Mercaptopurine?

Answer 41

bone marrow depression, jaundice and elevated liver enzymes, allopurinol toxicity

Question 42

How are 6-mercaptopurine and 6- TG given?

Answer 42

PO

Question 43

Does 6-TP have toxicity with allopurinol?

Answer 43

No, it has a slightly different metabolic pathway.

Other toxicities are similar

Question 44

How does Hydroxyurea work?

Answer 44

Hydroxyurea is a free radical scavenger that captures the transient free radical necessary for the conversion of ribonucleotides to deoxyribonucleotides, thereby preventing this final synthetic step and inhibiting cell division.

Question 45

Side effects of Hydroxyurea?

Answer 45

Drug toxicities are common to many other anticancer drugs, perhaps with the exception of maculopapular rash, dermatomyositis-like skin changes, peripheral erythema, facial erythema, skin cancer, skin ulceration and skin darkening that can occur with this agent.

Question 46

Finally, you should remember that most anticancer drugs possess both teratogenicity and an ability to make the male or female patients infertile. Under some circumstances, the harvesting and freezing of sperm and/or eggs can be used to overcome this problem if the surviving patient later considers having a child.

Answer 46

Finally, you should remember that most anticancer drugs possess both teratogenicity and an ability to make the male or female patients infertile. Under some circumstances, the harvesting and freezing of sperm and/or eggs can be used to overcome this problem if the surviving patient later considers having a child.