期刊
CANCER CHEMOTHERAPY AND PHARMACOLOGY
卷 81, 期 1, 页码 1-15出版社
SPRINGER
DOI: 10.1007/s00280-017-3473-8
关键词
Antifolate; Folate; Glycinamide ribonucleotide formyltransferase; Hypoxia; Proton-coupled folate transporter; Purine; Reduced folate carrier; Targeted therapy
资金
- National Cancer Institute, National Institutes of Health [R01 CA53535, R01 CA152316, R01 CA166711]
- Eunice and Milton Ring Endowed Chair for Cancer Research
- Duquesne University Adrian Van Kaam Chair in Scholarly Excellence
This review considers the promise of exploiting the proton-coupled folate transporter (PCFT) for selective therapeutic targeting of cancer. PCFT was discovered in 2006 and was identified as the principal folate transporter involved in the intestinal absorption of dietary folates. The recognition that PCFT was highly expressed in many tumors stimulated substantial interest in using PCFT for cytotoxic drug targeting, taking advantage of its high level transport activity under the acidic pH conditions that characterize many tumors. For pemetrexed, among the best PCFT substrates, transport by PCFT establishes its importance as a clinically important transporter in malignant pleural mesothelioma and non-small cell lung cancer. In recent years, the notion of PCFT-targeting has been extended to a new generation of tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine compounds that are structurally and functionally distinct from pemetrexed, and that exhibit near exclusive transport by PCFT and potent inhibition of de novo purine nucleotide biosynthesis. Based on compelling preclinical evidence in a wide range of human tumor models, it is now time to advance the most optimized PCFT-targeted agents with the best balance of PCFT transport specificity and potent antitumor efficacy to the clinic to validate this novel paradigm of highly selective tumor targeting.
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