Studies on the antitumor activity and biochemical actions of cyclopentenylcytosine against human colon carcinoma HT-29 in vitro and in vivo

Cyclopentenyl cytosine (CPEC) is cytotoxic to several tumor cell lines. CPE C inhibits CTP synthesis resulting in depletion of cytidylate pools. The ai m of this study was to examine CPEC's cytotoxic and antitumor activity in v itro and in vivo against human colon carcinoma HT-29, and to relate its act ion on CTP synthesis. CPEC exhibits potent cytotoxicity in vitro to HT-29 c ells with an LC50 (concentration that is lethal to the survival of 50% cell colonies) of 2.4 mu M and 0.46 mu M following 2 h and 24 h exposure, respe ctively. Incubation of cells with CPEC for 2 h resulted in a dose-dependent decrease in cytidylate pools. The in vivo antitumor activity of CPEC in at hymic mice transplanted subcutaneously (S.C) with 3 million MT-29 cells was examined. Antitumor activity of CPEC was elucidated in early-staged tumor, wherein CPEC (1.5 mg/kg, QD x 9 or 3 mg/kg, QOD x 9) was administered intr aperitoneally (i.p.) 24 h after tumor implantation and it resulted in a sig nificant reduction in tumor weight to 48% of control. The effect of CPEC on established solid tumors in vivo was examined in athymic mice transplanted s.c. 14 days earlier with MT-29 cells and treated i.p. with 1.5 mg/kg CPEC , QD x 5 for 4 courses, with a 10 day-interval between courses. This treatm ent resulted in a significant reduction in tumor weight (72%) in the treate d group. HPLC analysis of HT-29 tumor obtained from mice after treatment wi th OPEC showed a depletion of the CTP concentration reaching a nadir at 8 h . In conclusion, the present studies demonstrate potent antitumor activity of CPEC against freshly transplanted and established human colon carcinoma which can be corroborated with the drug's biochemical actions.