PREVENTION OF CISPLATIN NEUROTOXICITY WITH AN ACTH(4-9) ANALOG IN PATIENTS WITH OVARIAN-CANCER

In a randomized, double-blind, placebo-controlled study, we assessed the efficacy of an ACTH(4–9) analogue, Org 2766, in the prevention of cisplatin neuropathy in 55 women with ovarian cancer. The analogue was given subcutaneously in a dose of 0.25 mg (low dose) or 1 mg (high dose) per square meter of body-surface area before and after treatment with cisplatin and cyclophosphamide (75 and 750 mg per square meter every three weeks). The threshold of vibration perception was used as the principal measure of neurotoxicity. After four cycles of chemotherapy, the mean (±SEM) threshold value for vibration perception in the placebo group increased from 0.67±0.12 to 1.61±0.43 μm of skin displacement (P<0.0001). In the high-dose treatment group, there was no increase in the threshold value after four cycles (from 0.54±0.12 to 0.50±0.06 μm). After six cycles of chemotherapy, the threshold value was 5.87±1.97 μm in the placebo group (more than an eightfold increase from base line), as compared with 0.88±0.17 μm (less than a twofold increase) in the high-dose treatment group (P<0.005). In the high-dose group, fewer neurologic signs and symptoms were recorded than in the placebo group. With the lower dose of the analogue, these protective effects were less prominent. No side effects were seen after treatment with Org 2766. The rates of clinical response to chemotherapy were similar in all groups. These results suggest that Org 2766 can prevent or attenuate cisplatin neuropathy without adversely affecting the cytotoxic effect of the drug. MELANOCORTINS (ACTH and α-melanocyte-stimulating hormone-like peptides) are known to affect the function of the nervous system in animals and humans.1 Evidence obtained from studies in animals suggests that these peptides exert a beneficial effect on mechanisms of peripheral-nerve repair.2 After peripheral-nerve crush injury, ACTH and a number of derived fragments (Fig. 1) have been reported to accelerate recovery and enhance nerve regeneration in rats at the histologic, electrophysiologic, and functional levels.4 5 6 7 Recovery was also enhanced after transection of the nerve.8 The mechanism of action is not known, but evidence suggests the presence of an α-melanocyte-stimulating hormone-like substance in degenerating9 or… © 1990, Massachusetts Medical Society. All rights reserved.