Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dawn of chemotherapy for gastrointestinal cancers including colorectal cancer was the inception of 5-fluorouraci (l 5-FU), produced by Dr. Heidelberger in 1957. 5-FU had been playing the leading role in chemotherapy for colorectal cancer for four decades until the Nineties. The second wave of chemotherapy was biochemical modulation. For the enhancement of 5-FU effects, the sequential combination with methotrexate and leucovorin (LV) was devised. Among them, 5-FU/LV was established in standard chemotherapy for colorectal cancer, due to several meta-analyses. Oral 5-FU such as UFT, TS-1 and capecitabine derivatives are gaining an important position in chemotherapy for colorectal cancer based on the accumulation of evidence. The third wave enveloped chemotherapy. Irinotecan was developed for gastrointestinal cancer. In 2000, CPT-11+5-FU/LV became the standard and first-line chemotherapy for colorectal cancer in the U.S. and Europe. Unfortunately, we in Japan have lagged behind the U.S. and Europe, because, 5-FU with LV was not approved here until 1999. Oxaliplatin was accepted in Europe first. FOLFOX, including continuous infusion of 5-FU, and LV were approved in 1998. In 2004, oxaliplatin + 5-FU/LV, named FOLFOX 4, was approved as the first-line chemotherapy treatment for colorectal cancer in the U.S. Oxaliplatin was the synthesized in Japan. At last, it was approved with usage restrictions the past March. We are now able to use FOLFOX 4, and this chemotherapy strategy for colorectal cancer in Japan is spreading rapidly. Recently, several new molecular targeted agents, which we call the fourth wave of chemotherapy, have been available in clinical studies,and promising data have been presented. Among them, evacizumab and cetuximab were tested in large phase III studies, their efficacies were upheld, and the drugs were approved in the U.S. Median survival time(MST) has been gradually prolonged through 5-FU/LV with irinotecan and oxaliplatin. Now, with the addition of molecular targeted agents, over 20 months of MST was reported.
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PMID:[Recent progress of chemotherapy for colorectal cancer]. 1635 22

Gastrointestinal cancer causes countless deaths every year due to therapeutic resistance. However, whether metabolic alterations contribute to chemoresistance is not well understood. In this study, we report that fatty acid (FA) catabolism was activated in gastrointestinal cancer cells treated with oxaliplatin, which exhibited higher expression of the rate-limiting enzymes carnitine palmitoyltransferase 1B (CPT1B) and CPT2. The clinical analysis also showed that high expression of these enzymes was associated with poor oxaliplatin-based chemotherapy outcomes in patients. Furthermore, genetic or pharmacological inhibition of CPT2 with perhexiline disturbed NADPH and redox homeostasis and increased reactive oxygen species (ROS) generation and cell apoptosis in gastrointestinal cancer cells following oxaliplatin treatment. Specifically, the combination of oxaliplatin and perhexiline significantly suppressed the progression of gastrointestinal cancer in cell-based xenograft and patient-derived xenograft (PDX) models. Mechanistically, CPT2 was transcriptionally upregulated by nuclear factor of activated T cells 3 (NFATc3), which translocated to the nucleus in response to oxaliplatin treatment. In summary, our study suggests that the inhibition of CPT-mediated FA catabolism combined with conventional chemotherapy is a promising therapeutic strategy for patients with gastrointestinal cancers.
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PMID:Inhibition of fatty acid catabolism augments the efficacy of oxaliplatin-based chemotherapy in gastrointestinal cancers. 3190 82