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

Abstract

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.

• 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
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 38 Issue 11 Pg. 1543-52 (Jul 2002) ISSN: 0959-8049 [Print] England
• PMID: 12110502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cross-Linking Reagents
• DNA, Neoplasm
• Nitrogen Mustard Compounds
• Prodrugs
• Tumor Suppressor Protein p53
• ZD 2767
• gamma-Glutamyl Hydrolase

Topics

• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Division (drug effects)
• Colorectal Neoplasms (drug therapy, pathology)
• Cross-Linking Reagents (metabolism)
• DNA, Neoplasm (metabolism)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Nitrogen Mustard Compounds (therapeutic use)
• Prodrugs (therapeutic use)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (metabolism)
• gamma-Glutamyl Hydrolase (therapeutic use)