Nitrobenzyl phosphorodiamidates as potential hypoxia-selective alkylating agents.
A series of novel nitrobenzyltetrakis(chloroethyl)phosphorodiamidates has been prepared, and its cytotoxicity has been evaluated against HT-29 cells under aerobic and hypoxic conditions and against murine bone marrow progenitor cells under aerobic conditions. All compounds were selectively toxic to HT-29 cells under hypoxic conditions, and the selectivity ratios varied from 1.6 to > 90. Analogs lacking either the nitro group or the tetrakis(chloroethyl) moiety were not cytotoxic, confirming that the presence of both nitro and incipient alkylating groups are essential for activity. Surprisingly, some analogs were far more toxic to bone marrow progenitors than to HT-29 cells under aerobic conditions, suggesting that other activation mechanisms must exist in these hematopoietic cells. Cytotoxicity increased with increasing depth in the HT-29 spheroid model, consistent with the preferential hypoxic toxicity of these compounds. Alkaline elution experiments showed a greater number of DNA interstrand cross-links under hypoxic compared to aerobic conditions. The extent of cross-linking in hypoxic cells was essentially identical to that produced by an equitoxic dose of melphalan, suggesting that the cytotoxicity of these compounds results from phosphorodiamidate release and alkylation of DNA.
Mulcahy
R T
RT
Department of Human Oncology, University of Wisconsin, Madison 53792.
Gipp
J J
JJ
Schmidt
J P
JP
Joswig
C
C
Borch
R F
RF
D000332:Aerobiosis; D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001854:Bone Marrow Cells; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry / Q000528:radiation effects; D005720:Gamma Rays; D006098:Granulocytes / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009578:Nitrobenzenes / Q000138:chemical synthesis* / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage; D010752:Phosphoramide Mustards / Q000737:chemistry* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D009578:Nitrobenzenes; D010752:Phosphoramide Mustards; D004247:DNA; D010100:Oxygen