Evaluation of the acute and subchronic toxic effects in mice, rats, and monkeys of the genetically engineered and Escherichia coli cytosine deaminase gene-incorporated Salmonella strain, TAPET-CD, being developed as an antitumor agent.
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| Abstract |
TAPET-CD, a genetically engineered Salmonella strain with chromosomal-incorporated cytosine deaminase (CD) gene, has been shown to selectively accumulate tumors, suppress tumor growth, and convert 5-fluorocytosine (5-FC, an antifungal agent) to the antitumor agent 5-fluorouracil (5-FU) in animals. The current studies investigated the safety of TAPET-CD, and TAPET-CD/5-FC combination, in animals. In C57BL/6 mice (n = 10 females/dose), the maximum nonlethal dose of TAPET-CD (intravenous [IV] bolus) was 1 x 10(6) colony-forming units (cfu)/mouse, or > 10,000 x that of wild-type Salmonella. In Sprague-Dawley rats (n = 4/sex/group), after treatment with 4 weekly cycles of TAPET-CD (an IV injection/cycle at 1 x 10(5), 3 x 10(5), 1 x 10(6), 3 x 10(6), or 1 x 10(7) cfu/rat on day 1) and 5-FC (per os twice daily [PO b.i.d.], 250 mg/kg on days 2-7/cycle), clinical signs and mortality were evaluated daily, body weight and clinical pathology weekly, and gross necropsy on day 29. No treatment-related toxicity, although occasional and mild clinical signs (e.g., dehydration), increased hepatic enzyme/function values and white blood cells, splenic enlargement, and bilateral red discoloration of the kidneys, were observed. In cynolmogus monkeys, Experiment 1 involved treatment with TAPET-CD (IV injection at 1 x 10(9) cfu/monkey). Clinical signs and mortality were evaluated daily, body weight weekly, and gross necropsy on days 2, 7, and 31 (1/sex/time point). Experiment 2 involved treatment with TAPET-CD (IV injection at 1 x 10(9) and 1 x 10(10) cfu/monkey in Groups 1 to 3 and Groups 4 to 6, respectively) on day 1 and 5-FC (PO b.i.d. at 250, 500, and 1000 mg/kg in Groups 1 to 3, and 500, 1500, and 0 mg/kg in Groups 4 to 6, respectively) on days 4 to 17 (n = 1/sex/group). Clinical signs and mortality were evaluated daily; body weight and clinical pathology on days 1, 2, 4, 14, and 18; body temperature on days 1, 4, and 18; ophthalmic examinations on days 3 and 17; and gross necropsy and histopathology on day 18. Experiment 1 indicated that TAPET-CD at 1 x 10(9) or 1 x 10(10) cfu/monkey was well tolerated, with only occasional mild clinical signs (i.e., emesis, vomiting, inappetance, loose/infrequent/absence of stool), increases in hepatic enzyme/function values, and splenic enlargement. Experiment 2 indicated that TAPET-CD/5-FC combination had a maximum tolerated dose (MTD) of 1 x 10(10) cfu/monkey for TAPET-CD and 500 mg/kg for 5-FC in monkeys. Supra-MTDs induced renal toxicity. In conclusion, TAPET-CD had a good safety profile (reflected by the extremely large amount of TAPET-CD needed to induce mortality or toxicity) in mice, rats, and monkeys. More adverse events were observed with TAPET-CD/5-FC combination when compared to TAPET-CD and these events were similar to the reported effects of 5-FU, suggesting the involvement of 5-FU.
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| Authors | K C Lee, L M Zheng, D Margitich, B Almassian, I King |
| Journal | International journal of toxicology (Int J Toxicol) 2001 Jul-Aug Vol. 20 Issue 4 Pg. 207-17 ISSN: 1091-5818 [Print] United States |
| PMID | 11563416 (Publication Type: Journal Article) |
| Chemical References |
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