Comparative evaluation of the acute toxic effects in monkeys, pigs and mice of a genetically engineered Salmonella strain (VNP20009) being developed as an antitumor agent

被引:25
作者
Lee, KC [1 ]
Zheng, LM
Luo, X
Clairmont, C
Fischer, J
Margitich, D
Turnier, J
Almassian, B
Bermudes, D
King, I
机构
[1] Vion Pharmaceut Inc, New Haven, CT 06511 USA
[2] Oread Inc, Farmington, CT USA
[3] Pathol Associates Int, Farmington, CT USA
关键词
attenuation; genetically engineered Salmonella strain; VNP20009;
D O I
10.1080/109158100225006
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The objective of these studies was to perform a comparative evaluation of the acute toxicity of VNP20009, a genetically engineered Salmonella strain, in monkeys, pigs, and mice. It is hypothesized that mice would be more susceptible than other animal species to the toxic effects of VNP20009, because mice are the most sensitive natural host for the parental wild-type Salmonella typhimurium strain. These studies also compared the virulence of VNP20009 and the parental Salmonella in mice. In Cynomolgus monkeys and Yorkshire pigs (n = 2/dose), various doses (expressed as colony forming units [cfu] per animal) of VNP20009, or vehicle, were administered as a single IV injection (similar to 1 ml/min). The body weight, body temperature, clinical signs, clinical pathology (serum chemistry and hematology), and ophthalmic examinations (only in monkeys) were evaluated at various times. Necropsy was performed on day 15 in the pigs, and necropsy and histopathology on days 8 or 15 in the monkeys. In C57BL/6 mice (n = 10/dose), various doses of VNP20009, or the parental Salmonella, were administered as a single IV bolus injection. The mice were observed daily over 3 weeks. The results from monkeys showed that VNP20009-related changes in clinical pathology were primarily confined to liver enzymes and liver function tests (i.e., cholesterol, triglyceride, alanine aminotransferase, and aspartate aminotransferase levels). Significant toxicological changes occurred only at the dose of 1 x 10(10) cfu/monkey, but not at the doses of 1 x 10(8) or 3 x 10(9) cfu/monkey. Gross necropsy and histology findings were primarily confined to the spleen (enlargement, weight increase, and reticuloendothelial hyperplasia), thymus (size and weight reduction and lymphoid depletion), mesenteric lymph node (enlargement), and lung (weight increase). Most of these necropsy and microscopic findings, which occurred mostly in the high-dose group, may be related to the physiological responses to infection, rather than related to the intrinsic toxicity of VNP20009. The results from pigs showed that VNP20009 induced toxicological effects only at the dose of 3 x 10(9) cfu/pig, but not at the doses of 3 x 10(8) or 3 x 10(10) cfu/pig. Both pigs treated with 3 x 10(10) cfu/pig died within the first 2 days post-treatment. Necropsy showed the presence of abdominal transudate fluid, skin blotching, and pulmonary- and gall bladder-associated edema. Therefore, the pig mortality may have been related to the physical damage induced by the sudden systemic presence of large amounts of suspension. The results from mice showed that VNP20009, at doses as high as 1 x 10(6) cfu/mouse, did not induce any mortality. A 30% mortality rate was induced by 3 x 10(6) cfu/mouse, and 100% mortality by 1 x 10(7) cfu/mouse. The parental Salmonella, at a dose of 1 x 10(2) or 3 x 10(2) cfu/mouse, induced a 100% mortality. In conclusion, the doses of VNP20009 that induced acute toxicity are very high, suggesting that VNP20009 may be a safe agent. The virulence is 50,000 x less in VNP20009 than the parental Salmonella.
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页码:19 / 25
页数:7
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