B34 Cancer chemo antimetabolites

Question 1

List the 3 classes of chemo anti-metabolites

Answer 1

Anti-folate drugs

Pyrimidine analogs

Purine analogs

Question 2

Anti-folate drugs

Answer 2

Methotrexate

Pemetrexed
Pralatrexate

Question 3

How are cancer treatments designed to minimize the development of drug resistance by the tumor?

Answer 3

By using short-term, maximally intensive therapy with combinations of drugs.

Question 4

Expression of what protein allows for multidrug resistance by tumors?

Answer 4

P-glycoprotein expression.

Question 5

General side effects of all antineoplastic drugs

Answer 5

Nausea, vomiting

Stomatitis

Marrow suppression and infections

Alopecia

Question 6

What agent is used to reduce chemotherapy associated neutropenia?

Answer 6

Filgrastim - Recombinant human granulocyte colony stimulating factor.
hG-CSF

Question 7

MoA of Methotrexate

Answer 7

Inhibits dihydrofolate reductase.

Question 8

MoA of Pemetrexed

Answer 8

Inhibits both DHFR and Thymidylate synthase directly.

Question 9

Methotrexate

Indications

Answer 9

1) Lymphomas:
- Acute Lymphocytic Leukemia
- Burkitt lymphoma
- NH Lymphoma

2) Autoimmune diseases:
- Rheumatoid arthritis
- Psoriasis, psoriatic arthritis
- Crohns

3) Ectopic pregnancies, and abortions

4) Trophoblastic tumors
- molar pregnancy
- choriocarcinoma

Question 10

Methotrexate SEs:

Answer 10

Megaloblastic anemia
Pancytopenia
- regular blood counts are required

Restrictive Pulmonary Fibrosis

Hepatotoxicity, cirrhosis
- regular liver enzyme monitoring

Potential for crystalluria from an MTX metabolite, patient needs to be well hydrated and urine alkalinized.

Standard antimetabolite SEs
Alopecia
Oral stomatitis, mucositis
GI irritation
Infections

Question 11

What are the pyrimidine analog chemo agents (5)

Answer 11

5-FU

Gemcitabin

Capecitabin

Tegafur

Cytarabine, ara-C, cytosine arabinoside

Question 12

5-FU

MoA

Indications

Answer 12

5-FU is a prodrug
Converted to 5-FdUMP, which inhibits Thymidylate synthase.

Other 5-FU metabolites can also act as DNA and RNA antimetabolites, being incorporated and terminating synth.

Rx:

• 1st line treatment for colorectal cancer
• Basal cell carcinoma
• Other solid tumors

Question 13

What agent is administered with 5-FU to increase its action?

Answer 13

Leucorvin,

Actually acts as a cofactor for 5-FdUMP inhibition of thymidylate synthase

Question 14

5-FU

Kinetics and SEs

Answer 14

5-FU can only be administered i.v. due to severe GI irritation, and potentially life threatening diarrhea.

Dihydropyrimidine dehydrogenase is an enzyme that metabolizes it, and patients have up to 6-fold range for this enz. activity.

Thus, 5-FU doses can vary, and knowing a patients DPD activity is helpful for dosing.

5-FU is metabolised in the liver, lung, and kidneys.

SEs:
Severe GI toxicity.
Diarrhea
Marrow suppression, pancytopenia, infections
Mucositis
Hyperpigmentation and photosensitive rashes.

Question 15

Gemcitabine

MoA and indications

Answer 15

Gemcitabine is a prodrug, a Citidine analog with two fluoride atoms

Deoxycytidine kinase generates difluorodeoxycytidine triphosphate, aka Gemcitabine-trisphosphate

Inhibits DNA synthesis.

Indications:
Pancreatic cancer and NSC-Lung cancer.

Kinetics:
Given IV

Question 16

Capecitabine

MoA and Kinetics

Answer 16

Capecitabine is a prodrug that is converted into its active metabolite, 5-FU.

The enzyme performing the final step to generate 5-FU is - thymidine phosphorylase -
It is expressed highly by tumor cells, allowing Capecitabine to have somewhat tumor specific toxicity, and then the 5-FU inhibits - thymidylate synthase-

Kinetics:
Is given -orally- and well absorbed.
Metabolized to 5-FU by many steps, involving the liver and then finally the tumor cells.

Question 17

Capecitabine

Indications

Answer 17

Colorectal cancer

Metastatic breast cancer.

Question 18

Cytarabines other names

Answer 18

Cytarabine

Cytosine arabinoside

ara-C

Question 19

Cytarabine

MoA, Indications

Answer 19

Cytarabine is a deoxycytidine analog where the ribose sugar is replaced by arabinose.

Cytarabine is taken into cells then phosphorylated to ara-CTP.

ara-CTP inhibits DNA polymerase and can be incorporated to terminate chain elongation.

Rx:
Myeloid Leukemias
NH-lymphoma

Question 20

Ara-C

kinetics and SEs

Answer 20

Kinetics:
Is ineffective orally, due to deamination in the GI tract.

When given IV it does not penetrate the CNS. So must be given intrathecally if this is desired.
Can be given intrathecally to specifically target the CNS.

It is deaminated throughout the body and both Ara-C and its inactive metabolites are excreted in urine.

SEs:
Marrow suppression
Mucositis
CNS effects if given intrathecal. 
  -insomnia, fatigue
  -memory loss, confusion
  - dizziness, nausea

Question 21

What are the purine analog drugs. (4)

Answer 21

Fludarabine

Nelarabine

6-Mercaptopurine

6-Thioguanine

Question 22

Fludarabine

MoA and indications

Answer 22

A prodrug, with a adenine base and a arabinose sugar.
Converted in the cell by deoxycytidine kinase to the trisphosphate form.

Incorporated to both DNA and RNA, inhibiting synthesis.

Rx:
Lymphomas, 
CLL
Hairy cell leukemia
NH-lymphoma

Question 23

Fludarabine

Kinetics

Answer 23

Kinetics:
Only given orally, or it is metabolized in GI to a very toxic metabolite.
Excreted partially by the kidney

Question 24

Nelarabine

MoA, indications, SEs

Answer 24

Nelarabine is a prodrug for
araGTP

Indications:
Resistant T-cell lymphomas,
ALL
T-cell lymphomblastic lymphomas

SEs:
the usual, plus severe CNS toxicity

Question 25

6-MP MoA Indications

Answer 25

6-Mercaptopurine is converted to 6-thioinosinic acid, or TIMP, by HGPRT. 1) TIMP inhibits de novo purine synthesis, at the first step, Glutamine phosphoribosyl pyrophosphate amidotransferase. - Inhibits IMP synthesis 2) TIMP is also converted to thio-guanine monophosphate. Its derivatives can be incorporated to both DNA and RNA, rendering them nonfunctional. 3) thio-guanine also accumulates and inhibits IMP dehydrogenase, preventing GMP generation. Rx: - 1st line for ALL. - 2nd line DMARD for RA - Also used for Inflammatory Bowel Diseases to induce or maintain remission.

Question 26

What is the prodrug for 6-MP?

Answer 26

Azathioprine

Question 27

6-MP kinetics and SEs

Answer 27

It has unpredicatable oral bioavailability, but can be given orally. It does not pass into the CNS. It is metabolized by the Liver, in a reaction that is catalyzed by Xanthine Oxidase - - effects are inreased by Fubuxostat, allopurinol. - Must reduce 6-MP dose by 75% if also on allopurinol. SEs: Marrow suppression - regular blood counts required Liver damage - regular LFT monitoring Pancreatitis - check pancreas enzymes too Infections and Zoster reactivation.

Question 28

6-thioguanine | MoA, indications

Answer 28

aka Tioguanine, aka another downstream metabolite of 6-MP Forms GMP analog that is incorporated to DNA and RNA, toxic antimetabolite. Also inhibits GMP syntehsis via IMP dehydrogenase. Rx: Also for lymphomas, ALL and CLL, AML too. It is not metabolized by XO, so can be used instead of 6-MP for patients on allopurinol treatment. Not indicated for long term use in DMARDs or IBDs like 6MP. Too many long term side effects. SEs are the same as 6-MP.