org-2766 and Adenocarcinoma

The efficacy of the ACTH (4-9) analogue Org 2766 in the prevention of subclinical cisplatin neuropathy was assessed in a double-blind placebo-controlled multi-centre study in patients with testicular cancer or adenocarcinoma of unknown primary. Forty-two patients received at least four cycles of cisplatin (100 mg/m2 per cycle), together with subcutaneous injections of Org 2766 (2 mg/day for 5 consecutive days) or placebo. Vibratory threshold was used as a measure of neuropathy. For each individual patient, the influence of cisplatin on vibratory perception was quantified by the slope of the regression line between the natural logarithm of the vibratory thresholds and the number of cycles. From the slopes, the proportional increase of vibratory threshold per cycle of cisplatin was calculated. On average, vibratory thresholds increased by 42% with each cycle of 100 mg/m2 of cisplatin in the placebo group, and by 19% during treatment with Org 2766. The influence of cisplatin on vibratory thresholds was highly significant in the placebo group (P < 0.0001), and of borderline significance in the group treated with Org 2766 (P = 0.06). The difference in slopes between the two groups was of borderline statistical significance (Wilcoxon's two-sample test: P = 0.06; analysis of variance: P = 0.04). These results show that Org 2766 cannot completely prevent cisplatin neuropathy in young men with testicular cancer, but nerve damage may be ameliorated by the use of this ACTH (4-9) analogue.

Topics: Adenocarcinoma; Adolescent; Adrenocorticotropic Hormone; Adult; Anticonvulsants; Cisplatin; Double-Blind Method; Humans; Injections, Subcutaneous; Male; Middle Aged; Neoplasms, Unknown Primary; Peptide Fragments; Peripheral Nervous System Diseases; Sensory Thresholds; Testicular Neoplasms

In rats chronic systemic treatment with cisplatin results in a sensory neuropathy as evidenced by a reduction in the sensory conduction velocity in the sciatic nerve. Concomitant administration of the neurotrophic ACTH4-9 analog, ORG.2766, prevents the occurrence of the neuropathy. In addition, treatment with ORG.2766 stops further deterioration and improves recovery of an already established cisplatin-induced neuropathy. Furthermore, concomitant administration of ORG.2766 during a first cisplatin treatment period results in a better resistance against neurotoxicity in a second exposure period. Finally, ORG.2766 was shown not to hamper the anti-tumor effect of cisplatin in mice, carrying implanted tumor cells from a FMa human tumor line. These data are discussed in view of the potential clinical use of ORG.2766 in prevention and treatment of cisplatin-induced neuropathy.

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Animals; Anticonvulsants; Cisplatin; Female; Mice; Mice, Nude; Motor Neurons; Neural Conduction; Neurons, Afferent; Peptide Fragments; Rats; Rats, Inbred Strains; Time Factors