Abstract
Lonidamine is a substituted indazole carboxylic acid with a unique mechanism of action and early clinical studies have reported anti-tumour activity. In a phase II study 32 patients with previously treated advanced breast cancer were given Lonidamine in a daily divided oral dose of 600 mg. Of 28 patients evaluable for response, three (11%) achieved a partial response (4-24+ months) and three (11%) a minor response. Two patients have stable disease (greater than 3 months) and 20 progressed. Toxicity was very mild. Sixteen (53%) of 31 patients had myalgia which lasted a median of 2 weeks. This was investigated with nuclear magnetic resonance spectroscopy in four patients but the changes were unrelated to the degree of myalgia. No other major side-effect was seen, and no dose reduction was required. Lonidamine pharmacokinetics have been investigated in 17 patients 1 month after the start of therapy. Lonidamine was detected in the plasma of all patients, but there was no clear relationship between Lonidamine levels and clinical response or toxicity. Lonidamine appears to be active against advanced breast cancer and its low toxicity would allow combination studies with chemotherapy.
Highlights
In phase I studies of oral Lonidamine the most frequent side effects were myalgia, asthenia and somnolence (Weiss et al, 1985)
In view of the effects of Lonidamine on mitochondria we have examined a small series of patients by in vivo 31P nuclear magnetic resonance spectroscopy (31P NMRS) to investigate a possible link between myalgia and high energy phosphate metabolism. 31P NMR has been successfully applied to the investigation of normal and diseased muscle metabolism (Cresshull et al, 1981; Radda 1986)
Between June 1988 and May 1989, 32 patients with histologically proven advanced breast cancer were entered into the study
Summary
In phase I studies of oral Lonidamine the most frequent side effects were myalgia, asthenia and somnolence (Weiss et al, 1985). Myalgia was the dose limiting toxicity and occurred at a dose of 300-400 mg m-2 (Band et al, 1984; Band et al, 1986; Weinerman et al, 1986). Of particular interest was the complete lack of myelosuppression and alopecia. On the basis of these studies Lonidamine, 600 mg daily in divided doses, has been selected for phase II studies
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