DNA interstrand cross-linking and TP53 status as determinants of tumour cell sensitivity in vitro to the antibody-directed enzyme prodrug therapy ZD2767.
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.
Monks
Noel R
NR
Cancer Research Unit, University of Newcastle, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK.
Blakey
David C
DC
East
Simon J
SJ
Dowell
Robert I
RI
Calvete
Joanne A
JA
Curtin
Nicola J
NJ
Arris
Christine E
CE
Newell
David R
DR
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003432:Cross-Linking Reagents / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D011623:gamma-Glutamyl Hydrolase / Q000627:therapeutic use*
D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; D016159:Tumor Suppressor Protein p53; C097602:ZD 2767; D011623:gamma-Glutamyl Hydrolase