Possible Interaction: Cisplatin and Folate

“ResultsAdenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels.”

“Since it is known that folate metabolism might interfere with cisplatin effectiveness, we intended to study the influence of the Gamma Glutamyl Hydrolase -401C>T polymorphism in treatment response in cervical cancer.”

“ CDDP can inhibit methionine-uptake into tumor cells and cause depletion of folate cofactors including 5-CH3FH4 and FH4, which are essential for the formation of a ternary complex with thymidylate synthetase and 5-fluorodeoxyuridine, an active metabolite of 5-FU.”

“The pretreatment with CDDP increased the poolsize of CH2-H4 folate and H4 folate and increased the binding of FdUMP to the dTMP synthase of an intact cells.”

“For instance, cisplatin triggered preferentially p53 and folate biosynthesis while the ruthenium complex induced endoplasmic reticulum stress and trans-sulfuration pathways.”

“Total folate levels by cotreatment with CDDP was increased to 1.5-fold compared to 5-FU alone, whereas DPD activity and 5-FU concentration were not changed by cotreatment of CDDP in vivo.”

“The results showed folate elevation only after administration of 100 mg/body of CDDP , both in the tumor and mucosa (p < 0.01).”

“This data would suggest that cisplatin resistance is associated with changes in folate metabolism.”

“These experiments demonstrate that cisplatin can increase the availability of the reduced folate necessary for tight binding of FdUMP to dTMP synthase, thus enhancing the cytotoxicity of the cisplatin and 5FUra combination.”

“These results suggest that CDDP significantly enhances FUra cytotoxicity by inhibiting intracellularL-methionine metabolism and consequently increasing the reduced folate pool in mammalian tumor models in vivo.”