Use of hydroxyurea to alter drug resistance of human tumor cells.

Abstract

Tumor cell resistance to cancer chemotherapeutic agents is a well-recognized problem for clinicians. Efforts are being made to develop agents that are not affected by cross-resistance to other drugs, as observed with the mdr phenotype. Other efforts are focused on reversing drug resistance to enhance chemotherapeutic intervention. Gene amplification accounts for one mechanism through which tumor cells develop drug resistance. Since amplified genes may be unstable, the elimination of these genes is likely to be a promising new target for cancer chemotherapy. The use of HU at low concentrations either to reestablish tumor sensitivity to chemotherapeutic agents or to decrease tumorigenicity, accomplished by the reduction of oncogene copy number, continues to be investigated. Studies thus far all report similar effects of noncytotoxic concentrations of HU on unstably amplified genes (EC DNA elimination), regardless of what gene is harbored on the EC DNA. The next essential step in the evaluation of HU-induced EC DNA elimination is to study the phenomena in vivo. In spite of extensive tissue distribution, HU appears to have pharmacokinetic properties, due to its short half-life, that may limit investigators' ability to study its use in prototype animal tumor models such as the nude mouse. In contrast, HU's half-life in humans (3.5 to 4.5 hours) [122] is comparatively longer, and therefore clinical trials may prove less troublesome.