Vector Targeting Makes 5-Fluorouracil Chemotherapy Less Toxic and More Effective in Animal Models of Epithelial Neoplasms

Abstract

PURPOSE: 5-fluorouracil (5-FU) has been combined in the past with other drugs for the combination chemotherapy for cancers of the breast, ovary, and colon. These drug regimens were limited by the fact that 5-FU fails to kill nondividing cancer cells at the doses that are safe to deliver. The goal of the present study is to test the feasibility of replacing 5-FU in established 5-FU combination chemotherapy with the Ad-LpCDIRESE1A/5-fluorocytosine (5-FC) system for the purpose of reducing toxicity and increasing efficacy. EXPERIMENTAL DESIGN: We have replaced 5-FU in the weekly combination of CPT-11, folinic acid (FA) and 5-FU chemotherapy by 5-FC and an adenoviral vector that carries the L-plastin (Lp) tumor-specific promoter-driven transcription unit encoding the cytosine deaminase gene linked to the E1A gene by an internal ribosomal entry site element. This combination is called "genetic combination therapy." The goal of using the vector was to decrease the toxicity to normal tissue and to increase the efficacy of therapy in the cancer cells by increasing the concentration of 5-FU sufficiently high that even nondividing cancer cells would be killed by 5-FU through its incorporation into mRNA and consequent inhibition of synthesis of functional proteins. We compared the in vivo efficacy of the genetic combination therapy with the conventional combination chemotherapy in a mouse colon cancer model. RESULTS: Both replication-competent and -noncompetent adenoviral vectors carrying an L-plastin-driven cytosine deaminase transcription unit when combined with 5-FC, CPT-11, and FA showed increased in vitro therapeutic activity that was significantly higher than that of the conventional chemotherapy combination. Tumor-bearing mice treated with the genetic combination therapy showed a statistically significant advantage in terms of increased response rate, response duration, survival, and reduced toxicity when compared with tumor-bearing mice treated with the conventional combination chemotherapy. CONCLUSIONS: Replacement of 5-FU in 5-FU-based combination chemotherapy with the Ad-LpCDIRESE1A vector and 5-FU reduces toxicity and increases efficacy. This is a concept that could be potentially applied widely for many forms of cancer treatment.