A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours.

PURPOSE: To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose. METHODS: R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1-5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmacokinetic studies. RESULTS: Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma. CONCLUSIONS: The recommended phase II doses are 850-1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes.

Phase I/II trial of gefitinib and oxaliplatin in patients with advanced colorectal cancer.

Colorectal cancers frequently overexpress the epidermal growth factor receptor. Gefitinib (Iressa), an inhibitor of the epidermal growth factor receptor tyrosine kinase, is synergistic with oxaliplatin in preclinical colon cancer models. The authors conducted a phase I/II trial of gefitinib plus oxaliplatin in patients with previously treated metastatic colorectal cancer. In the phase I portion, 14 patients received oxaliplatin 130 mg/m2 intravenously every 21 days and gefitinib orally daily at 1 of 2 dose levels: 250 mg/day (8 patients), and 500 mg/day (6 patients). There were no objective responses. Three patients (38%) in the 250-mg cohort experienced disease stabilization for a median of 12 weeks, and 1 patient in the 500-mg cohort had stable disease for 18 weeks. Nausea/vomiting and rash were dose limiting. The randomized phase II part of the trial, in which patients were to receive oxaliplatin with or without gefitinib, was canceled due to the inactivity of single-agent gefitinib observed in the phase I portion, and emergent phase III data regarding the minimal activity of single-agent oxaliplatin. The authors conclude that the combination of gefitinib plus oxaliplatin is inactive in advanced colorectal cancer.

Domestication and the behavior-genetic analysis of captive populations.

Captive environments are believed to produce behavioral changes in animal populations that may limit our ability to generalize back to natural populations. These behavioral changes are thought to be associated with one or both of the following: (a) changes in frequencies of genes or gene complexes due to the effects of inbreeding or to changes in selection pressure; (b) changes in development of the phenotype due to the effects of changes in environmental variables. Inbreeding leads to increase in homozygosity, that may result in developmental anomalies because of a breakdown in developmental homeostasis. Changes in selection pressure may disrupt coadapted gene complexes that have evolved in the wild. Often, domestication is believed to result in individuals that are "degenerate"; i.e. inferior to individuals in the wild. However, this notion has received no empirical support. In fact, if phenotype changes do occur under domestication, these are usually quantitative, not qualitative, in nature. We suggest that the study of the domestication process may reveal evolutionary principles that would be difficult to discover in other ways, and the zoological parks may be ideal situations for such research.