Effect of nitrosoureas on calmodulin activity in vitro and in mouse intestine in vivo

The effects of BCNU, CCNU, methyl-CCNU, streptozotocin, and chlorozotocin on calmodulin activity were studied in vitro and in vivo. Preincubation of BCNU, CCNU, and methyl-CCNU with calmodulin produced a concentration-dependent inhibition of in vitro calmodulin activity expressed as stimulation of cyclic nucleotide phosphodiesterase. Cyclohexylisocyanate produced a similar inhibition. Streptozotocin and chlorozotocin had no effect. Calmodulin inhibition by methyl-CCNU was dependent on the concentration of calcium in the preincubation mixture. Administration of methyl-CCNU or chlorozotocin IP to CF1 mice produced a dose-dependent inhibition of calmodulin activity in the small intestine. Methyl-CCNU produced a significant decrease in intestinal calmodulin activity as early as 1 h after treatment, an effect that persisted up to 52 h. Morphologic changes in the intestinal crypt epithelial cells were evident between 27 h and 5 days after treatment, but not earlier than 27 h. Renal and testicular calmodulin activity and morphology were unaffected. Although it was not possible to correlate the extent of calmodulin inhibition with severity of the intestinal lesions, the data suggested a relationship between reduced activity of calmodulin in a tissue and the ultimate appearance of lesions. This apparent interaction between an antitumor drug and calmodulin in vivo could have multiple implications for cancer chemotherapy.