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

Lookup NU author(s): Noel Monks, Professor Nicola Curtin, Dr Christine Arris, Professor Herbie Newell

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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 (IC50 0.04-2.2 μM) in colorectal tumour and non-small cell lung cancer (NSCLC) cell lines, and was more potent than a monofunctional ZD2767D analogue (colorectal cell lines - IC50 18-38 μM), synthesised 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×IC50/LC50) 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. © 2002 Elsevier Science Ltd. All rights reserved.


Publication metadata

Author(s): Monks, N., Blakey, D., East, S., Dowell, R., Calvete, J., Curtin, N.J., Arris, C.E., Newell, D.R.

Publication type: Article

Publication status: Published

Journal: European Journal of Cancer

Year: 2002

Volume: 38

Issue: 11

Pages: 1543-1552

Print publication date: 01/01/2002

ISSN (print): 0959-8049

ISSN (electronic): 1359-6349

URL: http://dx.doi.org/10.1016/S0959-8049(02)00111-9

DOI: 10.1016/S0959-8049(02)00111-9

PubMed id: 12110502


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