We propose to evaluate the feasibility of tumor-targeted therapy based on enzymes that are associated with invasiveness of tumors. The concept relies on elevated levels of hydrolytic enzymes in many tumors, including the RIF mouse tumor. Normally hydrolytic enzymes are contained in lysosomes; in tumors, however, hydrolytic enzymes are often released in the extracellular space. We plan to use water-soluble conjugates of drugs that become hydrophobic after deconjugation by tumor enzymes (limited washout) and that sensitizer tumor cells to hyperthermia at low concentrations. Regional heating should then increase differential tumor cell killing. Deconjugated drug that becomes trapped in normal tissue should have limited toxicity since these tissues are not heated. Specifically, we are evaluating differential deposition of 8- hydroxyquinoline (8-OHQ) in RIF tumors based on the deconjugation of 8-OHQ-glucuronide by tumor beta-glucuronidase. We found significantly higher glucuronidase activity in RIF tumors than in liver, kidney, duodenum, muscle or skin, both in tissue homogenates and in minced tissue fragments. 8-OHQ-glucuronide is nontoxic even at high concentrations and water soluble up to 10 mg/m1. However, the aglycone 8-OHQ is insoluble in water and is both a cytotoxin and a heat sensitizer in micromolar concentrations. Our preliminary data demonstrate free 8-OHQ in RIF tumors after acidifying tumors with glucose inary data demonstrate free 8-OHQ in RIF tumors acidifying tumors with glucose and injecting 8-OHQ-glucuronide i.p. Tumor acidification, using glucose loading, may enhance tumor glucuronidase activity (pH optimum=5), but should not affect normal tissues. Our principal objectives are the study of 1) cytotoxicity and heat sensitization by 8-OHQ and selected analogs, 2) measurement of 8-OHQ accumulation and localization in vivo (tumors and normal tissues), 3) methods for maximizing 8-OHQ trapping in tumors, and 4) evaluation of long-term tumor control by combinations of 8-OHQ and hyperthermia with and without X-irradiation. Methods include in vitro colony-forming ability, HPLC techniques for 8-OHQ quantitation in tissues, fluorescent microscopy for 8- OHQ localization, and TCD50/120 (or tumor volume) measurements for assessing tumor control.
| Mansouri, A; Henle, K J; Nutt, A K et al. (1991) New approaches to the study of tumor drug resistance. SAAS Bull Biochem Biotechnol 4:13-6 |
| Monson, T P; Henle, K J; Nagle, W A et al. (1991) Tumor-targeted delivery of 8-hydroxyquinoline. Int J Radiat Oncol Biol Phys 20:1263-71 |
| Henle, K J; Shmookler Reis, R J; Lumpkin, C K (1991) Modulation of cellular glycosidase activity by hyperthermia. Int J Hyperthermia 7:531-7 |
| Mansouri, A; Henle, K J; Nagle, W A et al. (1990) Tumor cell drug resistance and its reversal. SAAS Bull Biochem Biotechnol 3:91-6 |
| Henle, K J; Monson, T P; Stone, A (1990) Enhanced glycosyltransferase activity during thermotolerance development in mammalian cells. J Cell Physiol 142:372-8 |
| Henle, K J; Norris, J S; Lumpkin, C K (1990) Heat-induced protein dephosphorylation in Chinese hamster ovary cells. Biomed Biochim Acta 49:35-44 |
| Henle, K J; Nagle, W A; Bedford, J S et al. (1990) Protein glycosylation in heat-sensitive and thermotolerance-deficient mutants of Chinese hamster ovary cells. J Cell Sci 95 ( Pt 4):555-61 |
| Neilan, B A; Henle, K J (1989) In vivo response of murine RIF tumors to thermochemotherapy. J Med 20:107-12 |
| Henle, K J; Nagle, W A; Norris, J S et al. (1988) Enhanced glycosylation of a 50 kD protein during development of thermotolerance in CHO cells. Int J Radiat Biol Relat Stud Phys Chem Med 53:839-47 |
| Henle, K J; Monson, T P; Nagle, W A et al. (1988) Tumor-targeted cell killing with 8-hydroxyquinolyl-glucuronide. Radiat Res 115:373-86 |
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