org-2766 and Ovarian-Neoplasms

The neurological toxicity seen in patients treated with cisplatin in most cases concerns ototoxicity and peripheral neuropathy. Thus far, the pathogenesis of cisplatin neuropathy remains obscure. Yet the fact that cisplatin affects mainly the sensory peripheral nerve fibers points towards an involvement of the dorsal root ganglia. In a rat model of cisplatin neuropathy, following a cumulative dose of approx. 12 mg/kg cisplatin the sensory nerve conduction velocity began to slow as compared to age-matched controls. Peptides derived from ACTH and MSH are known to exert neurotrophic effects. In vivo they facilitate postlesion repair mechanisms in the peripheral nervous system by enhancing the early sprouting response of the damaged nerve. Surprisingly, chronic treatment with a synthetic ACTH4-9 analog not only prevented cisplatin neurotoxicity following a low or high dose regimen, but also counteracted already existing cisplatin-induced neurotoxicity. Stimulated by these findings a randomized, double blind, placebo-controlled study was performed to assess the efficacy of the peptide in the prevention of cisplatin neuropathy in women suffering from ovarian cancer. The threshold of vibration perception (VPT) was used as the principal measure of neurotoxicity. Following 6 cycles of chemotherapy the VPT had increased more than 8-fold in women receiving placebo as co-medication. Whereas the VPT in women receiving 1 mg/m2 body surface ACTH4-9 analog before and after each cisplatin cycle only increased less than 2-fold. No side effects of the peptide treatment were observed and the clinical response to the chemotherapy was similar in all treatment groups. Collectively these preclinical and clinical data suggest that treatment based on non-endocrine fragments of ACTH/MSH may be a therapeutic option in the treatment of cisplatin neuropathy.

Topics: Adrenocorticotropic Hormone; Amino Acid Sequence; Animals; Cisplatin; Female; Humans; Melanocyte-Stimulating Hormones; Molecular Sequence Data; Ovarian Neoplasms; Peptide Fragments; Peripheral Nervous System Diseases

Numerous experiments with peptides related to ACTH/MSH, and involving tests such as avoidance, approach, discrimination and rewarded behavior indicate that these peptides possess neuroactive effects on learning, motivation, attention, and concentration. In addition, ACTH/MSH neuropeptides affect social behavior, interact with opiate binding sites, and possess antiepileptic properties. Other CNS effects which can be demonstrated after intracranial administration only are grooming behavior, stretching, yawning and sexual behavior. The effects reside mainly in the N-terminal part of ACTH (ACTH-(4-10); ACTH-(7-16) and are dissociated from the peripheral corticotrophic effect. Several substitutions in the sequence ACTH-(4-9) led to a highly selective, potent and orally active neuropeptide with a marked loss of endocrine effects. Thus H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH (Org 2766) appeared to be 1,000 times more active on avoidance behavior than ACTH-(4-10) but to contain 1,000 times less melanotrophic activity. It also had a markedly reduced steroidogenic, fat mobilizing and opiate-like activity. ACTH/MSH peptides also possess neurotrophic activities as derived from studies on regeneration of damaged nerve cells. Animal studies show beneficial effects of semichronic treatment of the ACTH-(4-9) analogue Org 2766 on nerve crush regeneration in animals. The activity for this effect resides in the sequence ACTH-(6-10). The neurotrophic influence is evident both at the sensory and the motor function level. The protective effect of Org 2766 is also found in other neuropathies as a result of diabetes mellitus and chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Amino Acid Sequence; Animals; Anticonvulsants; Behavior, Animal; Brain; Cisplatin; Female; Humans; Melanocyte-Stimulating Hormones; Molecular Sequence Data; Neuropeptides; Ovarian Neoplasms; Peptide Fragments

The objective was to evaluate the efficacy of Org 2766 (a hexapeptide analogue of ACTH) in the prevention or delay of cisplatin-induced neuropathy during chemotherapy in women with ovarian cancer as measured by vibration perception threshold (VPT).. In this randomized, multicenter, double-blind, placebo-controlled study, 196 women with ovarian cancer were treated with cisplatin 75-100 mg/m2, cyclophosphamide 600-1000 mg/m2 plus placebo or two dose levels of Org 2766. The cisplatin-induced neuropathies were monitored by determining the VPT with the Vibratron II. VPT was determined for both the most sensitive great toe and the index finger on a monthly basis during treatment and months 1, 2, and 3 postchemotherapy. Once the blind was broken, it was found that 174 women (59 in placebo, 58 in 2 mg, and 57 in 4 mg) had enough data to allow evaluation.. Over the course of follow-up, the VPT was found to increase. This is consistent with the development of cisplatin-induced peripheral neuropathies. The baseline VPT for the index finger was less than that of the great toe (0.65 vs 2.13), but the percentage change in VPT was the same for both (percentage increase in VPT of about 350%). When the VPTs are compared according to the dose of Org 2766 given, there appears to be no difference in the rate of change or degree of neuropathies that developed in these women receiving cisplatin and cyclophosphamide.. The development of cisplatin-induced neuropathies is confirmed by measurement of the VPT. The rate of development of neuropathies seems to accelerate after the sixth course of cisplatin. When the development of neuropathies is evaluated on the basis of Org 2766 dosage, it is found that there is no difference in the rate or degree of neuropathies seen. Instead of providing protection from and delay of onset of peripheral neuropathies caused by cisplatin, these results suggest that the administration of Org 2766 appears to cause an increase in the rate of change and degree of neuropathies (P > 0.05).

Topics: Adrenocorticotropic Hormone; Antineoplastic Agents; Cisplatin; Double-Blind Method; Female; Humans; Middle Aged; Ovarian Neoplasms; Peptide Fragments; Peripheral Nervous System Diseases

Peripheral neuropathy is an important and disabling side-effect of cisplatin treatment. A new drug, Org 2766, has been found to prevent this neuropathy up to 1 month after treatment. A group of 18 patients with ovarian cancer, who participated in an earlier randomized study with placebo or Org 2766, together with cisplatin and cyclophophamide, were thereafter prospectively followed up to 2 years after discontinuation of treatment to monitor the development of neurological signs and symptoms and vibration perception threshold (VPT). Exploratory, descriptive data analysis shows that between 1 and 4 months after the last cycle the average sum score for neurological signs and symptoms and VPT had deteriorated compared with 1 month after treatment. Thereafter a gradual but incomplete improvement was seen between 4-12 and 12-24 months after treatment. These changes were seen in all patients regardless of previous treatment with Org 2766 or placebo, but deterioration was less pronounced in patients previously treated with Org 2766. These results suggests that treatment with Org 2766 to prevent a cisplatin-induced neuropathy should possibly be continued up to 4 months after the last cycle of cisplatin.

Topics: Adrenocorticotropic Hormone; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Cyclophosphamide; Double-Blind Method; Female; Humans; Ovarian Neoplasms; Peptide Fragments; Peripheral Nervous System Diseases; Sensory Thresholds; Vibration

The neurological toxicity seen in patients treated with cisplatin in most cases concerns ototoxicity and peripheral neuropathy. Thus far, the pathogenesis of cisplatin neuropathy remains obscure. Yet the fact that cisplatin affects mainly the sensory peripheral nerve fibers points towards an involvement of the dorsal root ganglia. In a rat model of cisplatin neuropathy, following a cumulative dose of approx. 12 mg/kg cisplatin the sensory nerve conduction velocity began to slow as compared to age-matched controls. Peptides derived from ACTH and MSH are known to exert neurotrophic effects. In vivo they facilitate postlesion repair mechanisms in the peripheral nervous system by enhancing the early sprouting response of the damaged nerve. Surprisingly, chronic treatment with a synthetic ACTH4-9 analog not only prevented cisplatin neurotoxicity following a low or high dose regimen, but also counteracted already existing cisplatin-induced neurotoxicity. Stimulated by these findings a randomized, double blind, placebo-controlled study was performed to assess the efficacy of the peptide in the prevention of cisplatin neuropathy in women suffering from ovarian cancer. The threshold of vibration perception (VPT) was used as the principal measure of neurotoxicity. Following 6 cycles of chemotherapy the VPT had increased more than 8-fold in women receiving placebo as co-medication. Whereas the VPT in women receiving 1 mg/m2 body surface ACTH4-9 analog before and after each cisplatin cycle only increased less than 2-fold. No side effects of the peptide treatment were observed and the clinical response to the chemotherapy was similar in all treatment groups. Collectively these preclinical and clinical data suggest that treatment based on non-endocrine fragments of ACTH/MSH may be a therapeutic option in the treatment of cisplatin neuropathy.

Topics: Adrenocorticotropic Hormone; Amino Acid Sequence; Animals; Cisplatin; Female; Humans; Melanocyte-Stimulating Hormones; Molecular Sequence Data; Ovarian Neoplasms; Peptide Fragments; Peripheral Nervous System Diseases

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 microns of skin displacement (P less than 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 micron). After six cycles of chemotherapy, the threshold value was 5.87 +/- 1.97 microns in the placebo group (more than an eight-fold increase from base line), as compared with 0.88 +/- 0.17 micron (less than a twofold increase) in the high-dose treatment group (P less than 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.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Cisplatin; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Middle Aged; Ovarian Neoplasms; Peptide Fragments; Peripheral Nervous System Diseases; Random Allocation; Sensory Thresholds; Vibration

Topics: Adrenocorticotropic Hormone; Amifostine; Anticonvulsants; Cisplatin; Female; Glutathione; Humans; Nervous System Diseases; Ovarian Neoplasms; Peptide Fragments