Inhibition of proliferative growth in glioma cells by calmodulin antagonists

The effects of several calmodulin antagonists, such as N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide hydrochloride (W-7) and its dechlorinated structural analogue (W-5), on the growth and proliferation of cultured and transplanted glioma (GA-1, chemically induced from rat glioblasts) were evaluated. Under culture conditions, the concentration of W-7 necessary to exert 50% inhibition of GA-1 glioma cell growth was 50 microM. However, W-5, with a lower binding affinity to calmodulin than W-7, caused no definite inhibition of the proliferation of GA-1 cells in culture. When a low concentration of W-7 (12.5 microM) was added to the culture medium, deoxyribonucleic acid (DNA) synthesis in the GA-1 glioma cells was not markedly affected, whereas both ribonucleic acid (RNA) and protein syntheses were strongly suppressed on incubation for 24 hours. When a high concentration of W-7 (25.0 to 75.0 microM) was applied to the medium, synthesis of DNA, RNA, and protein was distinctly inhibited. When W-7 (50.0 microM) was added to the incubation medium, the calmodulin concentration in the cultured GA-1 was reduced to as much as half the control level within 2 hours, and thereafter remained at this level. Whereas control rats intraperitoneally transplanted with GA-1 cells could survive for 14 to 21 days, daily intraperitoneal injections of W-7 at concentrations of 1.0, 3.0, and 10.0 mg/kg body weight prolonged the survival span to between 21 and 26 days; this corresponded to an increased life span of about 40% compared to the controls.