Tumor-targeted cell killing with 8-hydroxyquinolyl-glucuronide.
Many tumors show elevated levels of hydrolytic enzymes that may be associated with invasive processes. The RIF-1 murine tumor has levels of beta-glucuronidase that are more than four times higher than those in liver. Elevated tumor glucuronidase levels can be used as a basis for tumor-targeted therapy when systemically administered glucuronides of cytotoxic drugs are deconjugated preferentially at the tumor site. In this study we have used 8-hydroxyquinoline (8-OHQ) as a model compound for such a tumor-targeting concept. We showed that RIF tumors and spleen had the highest beta-glucuronidase activity in C3H mice; for example, RIF tumors released approximately seven times more phenolphthalein per gram of tissue from its glucuronide than liver, when compared under identical conditions. In vitro, low concentrations of 8-OHQ that might be achievable in vivo, ranging from 1 to 10 microM reduced cell survival by four orders of magnitude, while 1 mM 8-hydroxyquinolyl-glucuronide (1 h, 37 degrees C) resulted in only modest (S = 54%) cytotoxicity. Combination treatments of 8-OHQ (2.5 or 5 microM) with either hyperthermia or X radiation did not significantly change the slope of survival curves for RIF tumors in vitro, but suggest that targeted 8-OHQ toxicity combined with local hyperthermia and/or irradiation may be useful for significantly increasing therapeutic gains in vivo.
D000818:Animals; D000970:Antineoplastic Agents; D003131:Combined Modality Therapy; D005966:Glucuronidase / Q000378:metabolism*; D006912:Hydroxyquinolines / Q000494:pharmacology*; D006979:Hyperthermia, Induced; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy; D015125:Oxyquinoline / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects
D000970:Antineoplastic Agents; D006912:Hydroxyquinolines; D015125:Oxyquinoline; D005966:Glucuronidase