1.   Antifolates

2.      Methotrexate (MTX)

3.      Pyrimidine Analogs

4.      Cytosine Arabinoside – (araC, cytarabine)

5.      Fluorouracil (5-FU)

6.      Purine Analogs

7.      Mercaptopurine (MP)

8.      Thioguanine (6-TG)

9.      Misc

10.    Hydroxyurea

11.    Rescue Drug (Not for CHEMO)

12.    Leucovorin

ALL OF THESE DRUGS ARE S-PHASE SPECIFIC and interfere with DNA synthesis

Antifolates – Methotrexate (MTX)

Methotrexate

• inhibits dihydrofolate reducatse (enzyme necessary for conversion of FH₂ to FH₄

Ø  depletes the intracellular pool of N5,10-MetheleneTHF which is required for conversion of dUMP to dTMP by thymidylate synthase

• Effects are self-limiting – because it inhibits more than just DNA synthesis (RNA, protein), it slows down the growth of the cancer cells which leads to decreased effectiveness
• Actively taken up into cell by transport system that also transports folate
• Polyglutamylated in the cell – “traps” and raises affinity for dhfr
• Rescue with Leucovorin – (N5-formyl FH₄)

Ø  because the tumor cells transport methotrexate poorly, high doses are given to saturate.

Ø  Taking advantage of the poor transport of MTX and folate, normal tissue cells take up the Leucovorin which is converted to N5, 10 – metheleneTHF

Ø  Important in use for osteogenic sarcoma

• Use: osteogenic sarcoma, Childhood ALL, choriocarcinoma, breast, head and neck
• Resistance: increased synthesis of dhfr, reduced uptake
• Oral administration, IV, IM, or intrathecally

Ø  intrathecal – because of poor CNS penetration – used for prophylaxis and treatment of leukemic meningitis

• In high doses: 7-OH-methotrexate (metabolite) can cause renal failure (alkalinize urine)
• DLT: Myelosuppression
• Other uses other than for cancer: Psoriasis and rheumatoid arthritis

Pyrimidine Analogs – Fluorouracil (5-FU), Cytosine Arabinoside (araC, cytarabine)

Fluorouracil

• Converted to FdUMP through many alternate pathways (p. 41)
• Forms stable ternary complex with thymidylate synthetase and methylene FH₄ to inhibit production of dTMP and thus inhibits synthesis of DNA
• Resistance: decreased conversion to FdUMP or altered thymidylate synthetase
• *Penetrates CNS
• * Inactivated in Liver (some have deficiency of enzyme)
• *Use: Breast, GI, and Skin (Premalignant keratoses& basal cell CAs)
• DLT: Myelosuppression (stomatitis and diarrhea are warning signs that you’ve got a sufficient dose)

Cytosine Arabinoside (araC, cytarabine)

• 2-deoxycytidine analog in which OH group is reversed
• incorporated in DNA
• must be activated to araU by deoxycytidine kinase
• inactivation: by cytidine deaminase in liver blood and tissues
• Resistance: deoxycytidine kinase deficiency, increased deaminase activity
• IV, intrathecally
• DLT: myelosuppression
• Use: main drug in treatment of acute myelogenous leukemia

Purine Analogs – Mercaptopurine (MP), 6-Thioguanine (6-TG)

General

• both are analogs of hypoxanthine and guanine
• both must be converted to thioIMP and thioGMP by the salvage pathway enzyme HGPRTase

Mercaptuporine (MP)

• *inhibits 1^st step in Purine biosynthesis ( feedback inhibition)
• also inhibits formation of AMP and GMP from IMP
• *inactivated in liver by xanthine oxidase to 6-thiouric acid
• *dose reduction with allopurinol (inhibits xanthine oxidase which increases the toxicity of 6-MP
• *Resistance: deficiency of HGPRTase
• *Given orally
• *Use: Maintenance therapy for ALL and CML
• some may be incorporated into the DNA
• DLT: bone marrow depression (occurs slowly)

Thioguanine (6-TG)

• *1^o mechanism of toxicity – incorporated into DNA
• *No dose reduction with allopurinol
• *Use: acute granulocytic leukemia
• also inhibits the formation of AMP and GMP from IMP

Misc – Hydroxyurea

Hydroxyurea

• inhibits ribonucleotide reductase in pyrimidine synthesis
• oral
• crosses BBB
• Use: myeloproliferative disorders including Chronic granulocytic leukemia
• Used to synchronize cells at G₁/S thereby sensitizing them to effects of radiation.

Tags: Antifolates, Cytosine Arabinoside, Fluorouracil, Hydroxyurea, Mercaptopurine, Mercaptuporine, Methotrexate, Purine Analogs, Pyrimidine Analogs, Thioguanine

This entry was posted on Sunday, August 16th, 2009 at 5:00 am and is filed under Pharmacology. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.