5-FU was first synthesized in 1957, and it has been the major cytotoxic agent used in the management of colorecdtal cancer scince then.
As a single agent , Its response rate is only 15 %1 . In an attempt to improve on this response rate and also survival figures, administration schedulues have been modified, biochemical modulators have been utilised and other drugs have been used in combination including cisplatin, N-(phosphoneacetly)-L-asparatic acid (PALA), thymidine, methotrexate , and leucovorin1-4 . Currently, modulation of 5-FU with leucovorin is widely used to treat advanced colorectal carcinoma. Its mechanism of action is via increasing the intracellular levels of reduced folate. This enhances the formation and retention of the 5-FdUMP/TS complex , thus increasing inhibition of DNA synthesis. However, its efficacy is still controversial , because this combination has not yet been shown to contribute significantly to an improvement in overall survival, despite advantages over 5-FU alone, in terms of objective responses 1,5-9. Additionally, severe and intolerable side effects have been observed using this therapy, limiting its application10-12. In Japan, clinical trial using oral administration of a prodrug of 5-FU (tegafur: 1-(2-tetrahydrofuryl)-5-fluolouracil) demonstrated slight clinical efficacy and mild toxic effects in patients with advanced colorectal carcinoma13. Additionally, Japanese national medical insurance did not allow the use of leucovorin in the treatment of colorectalcarcinoma untill 1999. Therefore, one of the authors (M.K) attempted to produce another effective chemotherapy using a 5-FU based combination. M.K designed a regimen of PMC in 1989, involving continuous i.v. infusion of 5-FU for 24h per week and oral administration of UFT (Taiho Pharmaceutical Co., Tokyo, Japan) twice a day for 5-7 days per week14,15, based on experiments using rat models by Fujii et al 16. UFT is a combination of tegafur , a prodrug of 5-FU, and uracil at a molar ratio of 1: 4 . DPD , a key enzyme in degradation of 5-FU into therapeutically inactive metabolites , catalyzes the reduction of 60-90% of administered 5-FU, and its catalytic activity correlates with the rate of 5-FU clearance. Uracil inhibits hepatic DPD, and thus enhances the plasma 5-FU level and antitumor activity of 5-FU 17. Our PMC regimen has drastically improved the prognosis of patients with advanced colorectal carcinoma over the past 10 years18,19. Inactivation of p53, found in 70% of colorectal carcinomas in humans, occurs late in the tumorigenic sequence. Therefore, p53 gene mutation is likely to be limiting factor for the malignant transformation of precancerous cells in the loss of heterozygosity(LOH) pathway. P53 mutational analysis appears to have definite prognostic value in advanced colorectal carcinoma20,21. Most studies show significantly lower survival rates for patients with p53-mutated tumors compared with those with the non-mutated (wild type) p53. PMC showed an improved prognosis of irradiated rectal carcinomas with p53 overexpression 14. This result suggested that the antitumor property of 5-FU is enhanced by rectal tumors with a loss of the p53-related apoptosis pathway.
Recently, an in vitro study showed that the efficacy of the PMC regimen is based on targeting at least two different phases of the cell cycle , regardless of the status of the p53 gene. Also, surgical specimens after PMC suggested the coexistence of mitotic catastrophe and apoptosis in surgical specimens22.
In this article, we will explore the efficacy and mechanism of PMC , and finally, strategies for feasible modification of PMC .
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