Penclomedine-induced DNA fragmentation and p53 accumulation correlate withreproductive cell death in colorectal carcinoma cells with altered p53 status

Penclomedine, a synthetic pyridine derivative, has documented antitumor act ivity and is being investigated in clinical trials. its mechanism of action is unknown although it may be metabolized to a free radical, DNA-reactive species. We previously reported that telomerase positive colorectal carcino ma (RKO) cells with abrogated p53 function were more sensitive to penclomed ine than were telomerase positive cells with wild-type p53. The present stu dy demonstrates that significant differences in DNA fragmentation in respon se to penclomedine were observed in RKO cells lacking functional p53 compar ed with RKO cells with normal p53 function. No differences in DNA fragmenta tion in response to ionizing radiation were seen in RKO cells with normal o r abrogated p53 function. RKO cells with functional p53 respond to penclome dine treatment with a dose-dependent increase in p53 protein levels. Howeve r, RKO cells with abrogated p53 function did not show any such change in p5 3 protein levels. Further, p53-independent increase of p21 was observed, al though the significance of this response remains uncertain. These studies s uggest that penclomedine may have a therapeutic advantage in killing cells that have abrogated D53 function.