org-2766 and Neoplasms

Dose-limiting toxicity secondary to antineoplastic chemotherapy is principally due to the inability of the drugs to differentiate between normal and malignant cells. This results in normal tissue damage, as well as the desired antitumour effect. Toxicity may be acute, as in cisplatin-induced nephrotoxicity or alkylating agent myelotoxicity and haemorrhagic cystitis, or cumulative, as in anthracycline-related cardiac toxicity or cisplatin neurotoxicity. The consequences of this often include serious adverse effects and the inability to deliver adequate dose-intensive therapy against the cancer. Chemoprotective agents have been developed to provide site-specific protection against normal tissue toxicity, without compromising antitumour activity. Several chemoprotective compounds have recently been developed, including dexrazoxane (ICRF-187), amifostine (ethiofos: WR-2721), mesna and ORG-2766. Initial results confirm their promise as selective protective agents, although further randomised trials are required to identify their optimal role when used alone or in combination with other toxicity modifiers, including haematopoietic growth factors, with the ultimate aim being adequate dose escalation of chemotherapy to overcome tumour resistance.

Topics: Adrenocorticotropic Hormone; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Drug Interactions; Humans; Mesna; Neoplasms; Peptide Fragments; Razoxane

Although cisplatin is one of the most important antitumor agents yet developed, associated toxicities continue to limit its potential usefulness. Depending on the cisplatin dose and method of administration, limiting toxicities may include nephropathy, ototoxicity, peripheral neuropathy, or even myelosuppression. Recent therapeutic strategies such as hypertonic saline have proven successful in reducing the incidence of renal insufficiency, thus allowing cisplatin dose escalation to the level of 200 mg/m2 per 28-day cycle. Unfortunately, ototoxicity and a cumulative dose-related peripheral neuropathy have recently emerged as additional dose-limiting toxicities. One method of optimizing the therapeutic index of cisplatin is the concurrent administration of chemoprotective or rescue therapy. Ideally, an effective rescue agent would selectively reduce cisplatin-related side effects without reversing its antitumor activity. Three chemoprotective agents currently undergoing evaluation--WR-2721 (ethiofos), DDTC (diethyldithiocarbamate), and ORG-2766--have demonstrated preclinical efficacy. Clinical trials now in progress suggest that each agent may offer unique advantages, but many questions remain regarding the optimal use of these agents.

Topics: Adrenocorticotropic Hormone; Amifostine; Anticonvulsants; Cisplatin; Ditiocarb; Humans; Inactivation, Metabolic; Kidney Diseases; Neoplasms; Peptide Fragments

The efficacy of Org 2766, an ACTH(4-9) analogue, on the recovery of cisplatin neuropathy of longstanding duration was investigated in a phase II study. Twenty-two patients were treated with Org 2766 during a period of 4 months and vibration perception threshold (VPT) and sum scores for neuropathic symptoms and signs were compared with pre-treatment values. No change in VPT could be detected. Although there was a small improvement of clinical measures for neuropathy, no clear evidence for repair could be obtained. These results indicate no beneficial effect of Org 2766 on recovery of a longstanding cisplatin neuropathy.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Anticonvulsants; Brain Diseases; Cisplatin; Female; Humans; Male; Middle Aged; Motion Perception; Neoplasms; Peptide Fragments; Prospective Studies; Treatment Outcome; Vibration