DNA interstrand cross-linking and TP53 status as determinants of tumour cell sensitivity in vitro to the antibody-directed enzyme prodrug therapy ZD2767

• DOI: 10.1016/s0959-8049(02)00111-9
• Publication Date: 2002-10-14T15:12:48Z
• Authors: Noel R. Monks; David C. Blakey; Simon J. East; Robert I. Dowell; Joanne A. Calvete; Nicola J. Curtin; Christine E. Arris; David R. Newell
• Keywords: Lung Neoplasms; Dose-Response Relationship, Drug; DNA, Neoplasm; gamma-Glutamyl Hydrolase; 03 medical and health sciences; Cross-Linking Reagents; 0302 clinical medicine; Carcinoma, Non-Small-Cell Lung; Nitrogen Mustard Compounds; Tumor Cells, Cultured; Humans; Prodrugs; Drug Screening Assays, Antitumor; Tumor Suppressor Protein p53; Colorectal Neoplasms; Cell Division

Cellular determinants of sensitivity to the bifunctional alkylating agent 4-[N,N-bis(2-iodoethyl)amino]phenol (ZD2767D), the active drug produced by ZD2767 antibody-directed enzyme prodrug therapy (ADEPT), were studied. The prodrug 4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl L-glutamic acid (ZD2767P)+activating enzyme carboxypeptidase G2 (CPG2) displayed growth inhibitory activity (IC(50) 0.04-2.2 microM) in colorectal tumour and non-small cell lung cancer (NSCLC) cell lines, and was more potent than a monofunctional ZD2767D analogue (colorectal cell lines-IC(50) 18-38 microM), synthesized for the first time. ZD2767P + CPG2 rapidly formed DNA-DNA interstrand cross-links (maximal at 10 min), and semi-quantitative analyses indicate that levels were similar in 3 of 4 cell lines studied (25-75 rad equivalents) at equitoxic (10 x IC(50)/LC(50)) concentrations. In matched HCT116 TP53 functional/non-functional cell lines, there was no significant difference in the sensitivity to ZD2767P+CPG2. Together, these results suggest that cellular sensitivity to ZD2767P+CPG2 is, in part, related to the levels of interstrand crosslinks, but that TP53 status does not markedly effect chemosensitivity.