Introduction
N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl (DPPE) is a diphenylmethane-derivative arylalkylamine, similar in structure to various H1-antihistamines and tamoxifen, that has the ability to antagonize histamine binding in microsomes and nuclei. Preclinical studies of DPPE indicate a wide variety of biological effects, including inhibition of concanavalin A?induced mitogenesis in normal mouse spleen cells and protection of rodent bone marrow from toxic doses of doxorubicin and fluorouracil. DPPE also has been observed to potentiate the cytotoxicity of several classes of chemotherapeutic agents, including doxorubicin. In vitro, DPPE potentiation of the cytotoxicity of doxorubicin, paclitaxel, and vinblastine in human colon cancer cells, has been linked to it acting as a substrate for the P-glycoprotein (P-gp) pump while in mice, when combined with anthracyclines, DPPE increased the cure rate of experimental tumours. In early phase I and II clinical trials DPPE, combined with single agents (including doxorubicin), showed evidence of activity in heavily pre-treated patients. A previous 23 patient study of DPPE with doxorubicin in anthracycline-naive women with metastatic breast cancer reported overall and complete responses rates of 69% and 30%, respectively, with an acceptable level of toxicity. On the basis of these findings, the National Cancer Institute of Canada Clinical Trials Group conducted a multicenter phase II trial of the DPPE/doxorubicin combination in anthracycline-naive women with metastatic breast cancer.