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새로운 안트라사이클린계 항암제 DA-125 의 생식독성연구 (2) 랫트 최기형시험
정문구(Moon Koo Chung),김종춘(Jong Choon Kim),김원배(Won Bae Kim),노정구(Jung Koo Rho) 한국응용약물학회 1994 Biomolecules & Therapeutics(구 응용약물학회지) Vol.2 No.1
DA-125, a new anthracycline antitumor antibiotic, was at dose levels of 0, 0.03, 0.1 and 0.3 mg/kg/day administered intravenously to Sprague-Dawley male rats from premating to mating period and to females from premating to early gestation period. Effects of test agent on general findings and reproductive performance of parent animals and embryonic development were examined. No treatment-related changes in clinical signs, body weight, food consumption and necropsy findings were observed in all groups of both sexes. At 0.3 mg/kg, a decrease in the weight of spleen was found only in male rats. Mating performance and fertility of parent animals were not adversely affected by all doses tested. Fl fetuses showed no changes related to treatment of DA-125, except that at 0.3 mg/kg, an increase in the resorption rate was seen. The results show that the no effect dose levels (NOELs) for general toxicity of parent animals and fetal development are 0.1 mg/kg/day and NOELs for reproductive capability are over 0.3 mg/kg/day.
새로운 안트라사이클린계 항암제 DA-125 의 생식독성연구 (1) 랫트 최기형시험
정문구(Moon Koo Chung),한상섭(Sang Seop Han),양중익(Jung Ick Yang),노정구(Jung Koo Rho) 한국응용약물학회 1994 Biomolecules & Therapeutics(구 응용약물학회지) Vol.2 No.1
DA-125, a new anthracycline antitumor antibiotic, was at dose levels of 0, 0.1, 0.3 and 1.0 mg/kg/day administered intravenously to pregnant Sprague-Dawley rats during the organogenetic period. Two-third of dams per group were subjected to caesarean section on day 20 of pregnancy and the remaining 10 dams per group were allowed to deliver. Effects of test substance on dams, embryonal development of F1 fetuses, as well as growth, behaviour and mating performance of F1 offspring were examined. 1. At 1 mg/kg, one out of the 10 dams showed difficult delivery. A decrease in food consumption, a loss in body weight and a decrease of spleen weight were found in this dose level group. At 0.3 mg/kg, difficult deliverys were observed in two out of the 10 dams. 2. At 1 mg/kg, an increased resorption rate and a decreased fetal weight were found. In addition, various types of external, visceral and skeletal malformations occurred at an incidence of 11.9, 41.8 and 14.5%, respectively. 3. At 1 mg/kg, body weight reduction, small eyeball, hydrocephalus and atrophy of sexual organs were observed in F1 offspring. One male pup receiving 0.3 mg/kg died on day 2 of lactation. The results show that the no-effect dose levels (NOELs) for dams and F1 offspring are 0.1 mg/kg/day and NOEL for F1 fetuses is 0.3 mg/kg/day.
Cyclophosphamide 의 면역독성 검출을 위한 in vitro 시험법의 개발
정태천(Tae Cheon Jeong),(Michael P . Holsapple),차신우(Shin Woo Cha),하창수(Chang Su Ha),한상섭(Sang Seop Han),노정구(Jung Koo Rho) 한국응용약물학회 1994 Biomolecules & Therapeutics(구 응용약물학회지) Vol.2 No.3
A splenocyte culture system supplemented with liver microsomes was developed to detect immunotoxic chemicals which require metabolic activation using cyclophosphamide as a positive standard. When liver microsomes were added to splenocyte cultures isolated from female B6C3F1 mice, the proliferation of splenocytes by lipopolysaccharide (LPS) was increased and the proliferation by concanavalin A (Con A) was decreased. However, when compared with each corresponding control, cyclophophamide was successfully activated to metabolites capable of suppressing lymphoproliferative responses. This suppression was clearly dependent upon the amounts of microsomes added and/or the concentration of cyclophosphamide exposed. In these cultures, the proliferation of splenocytes was suppressed when the cells were exposed to cyclophosphamide on the day of culture initiation. On the other hand, microsome was responsible for the increase in LPS mitogenicity and NADPH was responsible for the decrease in Con A mitogenicity. Finally, our present culture system was compared with the hepatocyte-splenocyte coculture system which we had developed earlier. We found that the hepatocyte-splenocyte coculture was better able to activate cyclophosphamide to metabolites capable of suppressing the antibody response to sheep erythrocytes. Although our present culture system was relatively poor to activate cyclophosphamide in cultures for antibody response, it will be useful as a simple screening method to detect suppression of certain in vitro immunotoxic parameters like LPS mitogenicity by chemicals which require metabolism.