Cystemustine INSERM.
Cystemustine is a chloroethyl-nitrosourea under develop-ment by INSERM as a potential anticancer drug. It is in phase II trials in France for malignant melanoma [207163], advanced neck and head cancer [207164], advanced renal cancer [207165], and colorectal cancer [207187]. Cystemustine appears to have moderate activity against malignant gliomas using a 60 mg/m2 dosing regimen as a second line therapy, following surgery, chemotherapy or radiotherapy. Cystemustine has potent antitumor activity in mice. It has a short plasma half-life which makes it potentially amenable to circadian scheduling in order to enhance tolerability and dose intensity. The influence of circadian dosing time on toxicity was first investigated in a total of 368 synchronized male B6D21F1 mice. Leukopenia was the main hematological effect encountered. The activity of O6-alkylguanine-DNA alkyltransferase (AGT) was studied in the liver of 31 additional mice obtained at six different circadian times. A large amplitude circadian rhythm characterizes both cystemustine toxicity and liver AGT activity in mice. This suggests that the AGT rhythm is an important mechanism of the chronopharmacology of cystemustine [203827].
Palmer
B
B
Auckland University, Cancer Research Laboratory, School of Medicine, Private Bag 92019, Auckland, New Zealand. b.palmer@auckland.ac.nz