• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.4
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• pp.799-804
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• 2009

Kamikaekyuk-tang(KMKKT), a formula of ten Oriental herbs, was orientally designed to promote vital energy, to remove blood stasis, and to decrease inflammation for treating cancers. KMKKT and its component had potent antiandrogen and androgen receptor activities in prostate cancer and also inhibited angiogenesis induced by basic fibroblast growth factor (bFGF) in human umbilical vein endothelial cells and suppressed the tumor growth in LLC-bearing mice, and liver metastasis of colon 26-L5 cancer cells, suggesting a potent cancer preventive agent. Nevertheless, there is no safety study of KMKKT before clinical trial so far. Thus, in the current study, we investigated the toxicity about ethanol-extracted KMKKT. Male and female Spraque Dawley (SD) rats were given orally by KMKKT at 250, 500, and 1000 mg/kg for 4 weeks. Mortality, clinical signs and measured change of body weight, food consumption and water consumption were observed. In addition, we performed ophthalmologic, urinary, hematological, blood serum biochemical and histopathological examination. Any general toxicity was not found in KMKKT treated group. Also, there were no significant differences in the parameters such as body weight, food consumption and water consumption, a lot of urine and blood factor levels except WBC, MCHC and Ca level compared with control group. Although WBC and MCHC were elevated in female rats and Ca level was decreased in male rats, these were within normal ranges. Finally, we determined that maximum tolerated dose (MTD) was 1000 mg/kg and no observed adverse effect level (NOAEL) was 500 mg/kg. Taken together, these results demonstrated that KMKKT is very safe to SD rats.

• Archives of Pharmacal Research
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• v.21 no.5
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• pp.581-590
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• 1998

We developed a novel water-soluble camptothecin analobue, CKD602, and evaluated the inhibition of topoisomerase I and the antitumor activities against mammalian tumor cells and human tumor xenografts. CKD602 was a nanomolar inhibitor of the topoisomerase I enzyme in the cleavable complex assay. CKD602 was found to be 3 times and slightly more potent than topotecan and camptothecin as inhibitors of topoisomerase, respecitively. In tumor cell cytotoxicity, CKD602 was more potent than topotecan in 14 out of 26 human cancer cell lines tested, while it was comparable to camptothecin. CKD602 was tested for the in vivo antitumor activity against the human tumor xenograft models. CKD602 was able to imduce regression of established HT-29, WIDR and CX-1 colon tumors, LX-1 lung tumor, MX-1 breast tumor and SKOV-3 ovarian tumor as much as 80, 94, 76, 67, 87% and 88%, respectively, with comparable body weight changes to those of topotecan. Also the therapeutic margin (R/Emax: maximum tolerance dose/$ED-{58}$) of CKD602 was significantly higher than that of topotecan by 4 times. Efficacy was determined at the maximal tolerated dose levels using schedule dependent i.p. administration in mice bearing L1210 leukemia. On a Q4dx4 (every 4 day for 4 doses) schedule, the maximum tolerated dose (MTD) was 25 mg/kg per administration, which caused great weight loss and lethality in <5% tumor bearing mouse. this schedule brought significant increase in life span (ILS), 212%, with 33% of long-term survivals. The ex vivo antitumor activity of CKD602 was compared with that of topotecan and the mean antitumor index (ATI) values recorded for CKD602 were significantly higher than that noted for topotecan. From these results, CKD602 warrants further clinical investigations as a potent inhibitor of topoisomerase I.

• Biomolecules & Therapeutics
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• v.2 no.2
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• pp.190-205
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• 1994

This study was conducted to investigate the repeated dose toxicity of DA-125, a new anthracycline antitumor antibiotic, in rats. Before the 13-week main study, a 4-week dose-range finding (DRF) study was carried out. The administration of DA-125 intravenously at dosage levels of 0, 0.125, 0.5, 2.0, and 8.0 mg/kg/day to rats for 4 weeks resulted in premature deaths of all animals in the 8.0 mg/kg/day group and in the deaths of 4 males and 4 females at 2.0 mg/kg/day. Body weights were markedly reduced in the 8.0 mg/kg/day group and showed dose-related decreases in all treatment groups when compared with the control group. Reductions in weight gain were slight and not significantly different at 0.125 mg/kg/day but animals receiving 0.5 mg/kg/day showed more marked decreases in gain in a clear dose-related manner Based On the results of the above DRF study, a 13-week repeated dose intravenous toxicity study in rats with DA-125 was performed at a dose level of 0, 0.012, 0.08 and 0.3 mg/kg/day. No treatment related effects were noted in behavior or body weight in all treatment groups. One male at the highest dose level died on study day 26, but the death could not be related to test article toxicity. Swelling and scabbing of the ears was present in all of the groups, including the control group. There were no treatment related changes in the hematological, biochemical or urinalysis values in all treatment groups. Thymus weights were significantly reduced ill males receiving 0.3 mg/kg/day and they were sligltly, and not significantly, reduced in females of the same group. While there were no associated histological changes. Treatment related necrosis was found in the tail vein (injection site) at 0.08 and 0.3 mg/kg/day. On the basis of these results, the no observed effect level (NOEL) was 0.012 mg/kg/day and the maximum tolerated dose (MTD) was estimated to be more than 0.3 mg/kg/day under the conditions tested.