Doxorubicin and vincristine with methionine depletion contributed to survival in the Yoshida sarcoma bearing rats

Abstract

Several anti-cancer agents show increased toxicity if administered with methionine-depleting total parenteral nutrition (Met-deplete TPN). Changes in the cell cycle due to Met-deplete TPN were investigated, and then the enhancement of the anti-tumor effects of serial combinations of doxorubicin (ADM), a drug acting on late S-G2 phase and vincristine (VCR), an antimitotic drug, under Met-deplete TPN was also examined in the tumor-bearing rats. According to the fraction of labeled mitosis, within 3 to 4 days after the introduction of Met-deplete TPN in the ascites type Yoshida sarcoma (YS) -bearing rats, the cell cycle of the tumor cells showed marked delay and the fraction of labeled mitosis decreased to less than 70%. However, this delay was recovered immediately after methionine infusion, with on increase in the labeled mitotic cell population. In the experiment using solid type YS-bearing rats, ADM was administered intraperitoneally under Met-deplete TPN for 8 days, followed by intraperitoneal VCR administration with methionine-containing TPN for 3 days, and then fed on solid food and water ad libitum until death. This serial combination of Met-deplete TPN with ADM and VCR resulted in marked suppression of the tumor and prolonged survival in comparison to the control groups with a significant difference (p < 0.001) (generalized Wilcoxon test).