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Preclinical and clinical studies with combinations of pemetrexed and gemcitabine
1Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Abstract:
The novel antimetabolite pemetrexed inhibits the folate-dependent enzymes thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent is broadly active in a wide variety of solid tumors, including non-small cell lung, breast, bladder, head and neck, and ovarian cancers, as well as mesothelioma. Gemcitabine is a pyrimidine nucleoside antimetabolite that is approved worldwide for the treatment of pancreatic and non-small cell lung cancers, and bladder cancer outside the United States. In addition, gemcitabine is active against a broad range of tumors including breast, ovarian, and other cancers. Preclinical studies have shown cytotoxic synergy when pemetrexed is combined with gemcitabine. Based on these data, a phase I study of this combination was performed that showed striking activity. Phase II studies of this combination are being performed in breast and non-small cell lung cancer. In addition, a phase III study in pancreatic cancer is ongoing.
Insights
The combination of pemetrexed and gemcitabine shows promising activity in solid tumors. Clinical trials are evaluating this novel cancer treatment in various cancers, including lung, breast, and pancreatic.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Pemetrexed is a novel antimetabolite targeting key folate-dependent enzymes.
- Gemcitabine is an established pyrimidine nucleoside antimetabolite with broad anticancer activity.
- Both agents demonstrate efficacy in various solid tumors, including non-small cell lung cancer and breast cancer.
Purpose of the Study:
- To evaluate the cytotoxic synergy of combining pemetrexed and gemcitabine.
- To assess the clinical activity of the pemetrexed-gemcitabine combination in solid tumors.
Main Methods:
- Preclinical studies investigated the synergistic effects of pemetrexed and gemcitabine.
- Phase I clinical trials assessed the safety and activity of the combination.
- Ongoing Phase II and III trials are evaluating the combination in breast, non-small cell lung, and pancreatic cancers.
Main Results:
- Preclinical data indicated significant cytotoxic synergy between pemetrexed and gemcitabine.
- Phase I studies demonstrated striking activity for the combination therapy.
- Ongoing trials are further investigating the efficacy in specific cancer types.
Conclusions:
- The combination of pemetrexed and gemcitabine exhibits promising preclinical synergy and clinical activity.
- Further clinical evaluation in Phase II and III trials is warranted for various solid tumors.
- This combination represents a potential novel therapeutic strategy for cancer treatment.
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