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Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors
A R Hanauske1, V Chen, P Paoletti
1Eli Lilly and Company, Indianapolis, Indiana 46285, USA. Hanauske.IND-Synergen@t-online.de
Abstract:
Pemetrexed disodium (ALIMTA), "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck. Pemetrexed inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. As a single agent, pemetrexed exhibits a moderate toxicity profile at a dose of 500 mg/m(2) by 10-minute infusion once every 21 days with myelosuppression being the dose-limiting toxicity. Folic acid added to the diet in preclinical studies reduced toxicities while maintaining antitumor activity. Based on this observation and clinical toxicities, folic acid and vitamin B(12) dietary supplementation has been recently introduced into all ongoing trials. Studies combining pemetrexed with other active chemotherapeutic agents demonstrate that these combination therapies may become important treatment regimens in a variety of cancer types. Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate.
Insights
Pemetrexed is a novel antifolate drug showing promise in various solid tumors. Dietary supplementation with folic acid and vitamin B12 is being studied to reduce its toxicities.
Area of Science:
- Oncology
- Pharmacology
Background:
- Pemetrexed disodium (ALIMTA) is a multi-targeted antifolate with demonstrated clinical activity across numerous solid tumors.
- It functions by inhibiting key folate-dependent enzymes crucial for purine and pyrimidine synthesis.
Purpose of the Study:
- To evaluate the clinical activity and toxicity profile of pemetrexed.
- To investigate the potential of dietary supplementation (folic acid and vitamin B12) to mitigate pemetrexed-induced toxicities.
- To explore the efficacy of pemetrexed in combination therapies for various cancer types.
Main Methods:
- Pemetrexed was administered at a dose of 500 mg/m(2) via a 10-minute infusion every 21 days.
- Myelosuppression was identified as the dose-limiting toxicity.
- Preclinical studies indicated that folic acid supplementation reduced toxicities while preserving antitumor activity.
Main Results:
- Pemetrexed demonstrated a moderate toxicity profile as a single agent.
- Folic acid and vitamin B12 supplementation have been incorporated into ongoing clinical trials based on preclinical and clinical observations.
- Combination studies suggest pemetrexed may be an important component of future cancer treatment regimens.
Conclusions:
- Pemetrexed is a promising multi-targeted antifolate with broad-spectrum activity in solid tumors.
- Dietary supplementation with folic acid and vitamin B12 is a strategy to improve the tolerability of pemetrexed therapy.
- Further clinical trials, including Phase III studies in mesothelioma and non-small cell lung cancer, are underway to further explore the potential of this agent.