B34 Cancer chemo antimetabolites Flashcards
List the 3 classes of chemo anti-metabolites
Anti-folate drugs
Pyrimidine analogs
Purine analogs
Anti-folate drugs
Methotrexate
Pemetrexed
Pralatrexate
How are cancer treatments designed to minimize the development of drug resistance by the tumor?
By using short-term, maximally intensive therapy with combinations of drugs.
Expression of what protein allows for multidrug resistance by tumors?
P-glycoprotein expression.
General side effects of all antineoplastic drugs
Nausea, vomiting
Stomatitis
Marrow suppression and infections
Alopecia
What agent is used to reduce chemotherapy associated neutropenia?
Filgrastim - Recombinant human granulocyte colony stimulating factor.
hG-CSF
MoA of Methotrexate
Inhibits dihydrofolate reductase.
MoA of Pemetrexed
Inhibits both DHFR and Thymidylate synthase directly.
Methotrexate
Indications
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
Methotrexate SEs:
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
What are the pyrimidine analog chemo agents (5)
5-FU
Gemcitabin
Capecitabin
Tegafur
Cytarabine, ara-C, cytosine arabinoside
5-FU
MoA
Indications
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
What agent is administered with 5-FU to increase its action?
Leucorvin,
Actually acts as a cofactor for 5-FdUMP inhibition of thymidylate synthase
5-FU
Kinetics and SEs
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.
Gemcitabine
MoA and indications
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
Capecitabine
MoA and Kinetics
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.
Capecitabine
Indications
Colorectal cancer
Metastatic breast cancer.
Cytarabines other names
Cytarabine
Cytosine arabinoside
ara-C
Cytarabine
MoA, Indications
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
Ara-C
kinetics and SEs
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
What are the purine analog drugs. (4)
Fludarabine
Nelarabine
6-Mercaptopurine
6-Thioguanine
Fludarabine
MoA and indications
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
Fludarabine
Kinetics
Kinetics:
Only given orally, or it is metabolized in GI to a very toxic metabolite.
Excreted partially by the kidney
Nelarabine
MoA, indications, SEs
Nelarabine is a prodrug for
araGTP
Indications:
Resistant T-cell lymphomas,
ALL
T-cell lymphomblastic lymphomas
SEs:
the usual, plus severe CNS toxicity
6-MP
MoA
Indications
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.
What is the prodrug for 6-MP?
Azathioprine
6-MP kinetics and SEs
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.
6-thioguanine
MoA, indications
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.
