Phase 1 study of high-dose hydroxyurea in lung cancer

Abstract

The in vitro chemosensitivity of a human lung cancer cell line to hydroxyurea (HU) was measured, and concentrations of 1 mM HU effected 99% inhibition of cell growth. Therefore, infusions designed to achieve serum levels of over 1 mM HU were assessed by escalating doses of hydroxyurea (HU) administered by continuous i.v. infusion at 3-weekly intervals in 18 patients with lung cancer. Dose increments from 24 g in 24 h to 48 g in 48 h were achieved. The dose-limiting toxicity at 48 g in 48 h was myelosuppression. Oral administration of HU did not result in sustained levels comparable to those achieved with continuous infusion. Two patients showed evidence of radiological response after three courses of treatment. Serum HU profiles were monitored after administration i.v. in 26 courses and after administration p.o. in 5 courses of treatment. A mean serum level of greater than 1 mM was achieved by 6 h and then maintained during treatment. The standard error of the mean area under the curve showed an overall 5% variation. HU can be given in doses up to 48 g in 48 h 3-weekly with manageable tissue and bone marrow toxicity, and the in vivo blood levels attained are equal to those necessary for effective cell inhibition in an appropriate in vitro model. This schedule provides a basis for combination studies with other cytotoxics or for use of HU as a DNA repair inhibitor.