• Biomolecules & Therapeutics
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• v.2 no.1
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• pp.94-101
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• 1994

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.

• Biomolecules & Therapeutics
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• v.1 no.2
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• pp.226-235
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• 1993

DA-125, a new anthracycline antitumor antibiotic, was administered to Sprague-Dawley rats intravenously for 4 weeks to investigate the repeated dose toxicity Focal alopecia was noted in three female rats receiving 1.0mg/kg/day. In rats receiving 1.0 mg/kg/day, weight gain decreased in both sexes after first or second week. Hematological examination revealed lower counts of total leukocyte and increased numbers of platelet after second week. At terminal necropsy, atrophy of thymus and spleen was observed. Lymphocytic depletion of thymus and atrophy of white pulp in spleen were observed microscopically. A decrease in the number of hematopoietic cells in the bone marrow and degeneration of germinal epithelia in testes were also observed. These treatment-related effects were mainly confined to rats receiving 1.0 mg/kg/day. And toxic effects with microscopic changes were not observed in rats receiving 0.2 mg/kg/day or 0.04 mg/kg/day.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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• pp.37-37
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• 1993

1) 급성독성시험: 랫드와 마우스 공히 투여후 5~6일에 농도의존적의 강한 독성이 발현 되었으며 표적장기로는 소화기계, 임파계, 조혈기계 등으로 나타났다. 랫드에서의 반수 치사량은 암수 각각 771.9(505.6~1178.4)mg/kg과 479.8(302.7~760.4)mg/kg이었으며 마우스에서는 암수 각각 527.4(393.7~701.1)mg/kg과 463.0(308.8~694.2)mg/kg 이었다. 2) 유전독성: S. typhimurium을 이용한 복귀돌연변이시험, CHL세포를 이용한 염색체이상 시험, 마우스에서의 소핵시험결과 DA-125는 돌연변이 유발능을 갖는 것으로 나타났다. 3) 국소자극성: 혈관주위주사에 의한 피부자극성 시험결과 DA-125는 adriamycin의 3배 용량에서 궤양, 괴사등 유사한 병변이 유발되었으나, 병변회복은 adriamycin에 비해 빠른 것으로 나타났다. 또한 토끼에서의 안점막자극시험 결과에서 DA-125는 실제적으로 자극이 없는 것으로 나타났다.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.313.1-313.1
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• 2003

DA-125, a novel anthracycline analog containing fluorine with decreased cardiotoxicity and increased antitumor activity of adriamycin (ADM), developed by Research Laboratories of Dong-A Pharmaceutical. DA-125, water soluble prodrug of M1, is a ${\beta}$-alanine derivative of M1 (FT-ADM). DA-125 was rapidly hydrolyzed to M1, and M1 was metabolized to both M2 and M3. (omitted)

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.68.3-69
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• 2003

Matrix metalloproteinases (MMPs) play an important role in tumor invasion and metastasis by extracellular matrix degradation. To analyze the effect of DA-125, a anthracyclin derivative, on the invasion or metastasis of cancer cells the expression of matrix metalloproteases (MMPs) was investigated in human fibrosarcoma HTl080 cells by RT-PCR or gelatin zymographic methods. As result, DA-125 suppressed the expression of MMP-2 and 9 as well as tissue inhibitor of metalloproteinase-1 (TIMP-1) TIMP-2 and MT1-MMP with a time- and dose-dependent manner. Inaddition, DA-125 inhibited cancer cell migration and colony formation, and also exhibited the inhibitory activities of invasion and motility with a matrigel and type I collagen assay. (omitted)

• Biomolecules & Therapeutics
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• v.2 no.1
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• pp.82-93
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• 1994

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 Fl fetuses, as well as growth, behaviour and mating performance of Fl 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 Fl 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 Fl offspring are 0.1 mg/kg/day and NOEL for Fl fetuses is 0.3 mg/kg/day.

• 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.

• Biomolecules & Therapeutics
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• v.8 no.1
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• pp.84-92
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• 2000

This Study was conducted to assess the single dose toxicity of DA-125, a new anthracycline anti-cancer agent, in rats and mice. The Drug was administered once intravenously to both sexes of rats and mice. Then followed a 14-day period of observation. The $LD_{50}$ Values (95% confidence limit) were estimated to be 60.9 mg/kg (57.5~64.3 mg/kg) for male rats and 60.2 mg/kg (56.2~64.5 mg/kg) for female rats, and 85.8 mg/kg (81.0~90.9 mg/kg) for male mice and 84.5 mg/kg (78.2~91.9 mg/kg) for female mice. Both sexes of rats and mice given the drug revealed the clinical sign of decreased locomotor activity, emaciation, hair loss, red-dish brown urine, salivation, and watery diarrhea. In addition, body weight from the next day to the 7th day tended to be decreased slightly in rats and mice treated with DA-125. Death occurred from the next day after administration to the 12th day. Macroscopically, congestion of gastrointestinal organ, lung, and adrenal glands were found in both sexes on the dead rats and mice. Histopathological examination of dead rats manifested atrophy of spleen, hypoplasia of bone marrow, hypcplasia and necrosis of lymphocyte in thymus, atrophy of villi in small intestine (duodenum, jejunum, and ileum), hyperplasia of granular epithelium in small intestine, degeneration of germinal epithelium in testis, defer oration of tubular epithelium in kidney, and vacuolation and myolysis of myocardium in heart. Histopathological examination of dead mice revealed hypoplasia of spleen and mesenteric lymph node, local necrosis of liver, atrophy of villi in small intestine, hyperplasia of glandular epithelium in small and large intestine, degeneration of tubular in kidney, degeneration of germinal cells in testis, and slight vacuolar degeneration of myocardium in heart.

• Toxicological Research
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• v.11 no.1
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• pp.69-75
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• 1995

The present study was carried out to establish several spermatotoxicity test methods. For this purpose we investigated following parameters in the fertility study of DA-125, a new anticancer agent, in rats: testicular spermatid counts, epididymal sperm counts, daily sperm production rate, sperm morphology, and serum testosterone concentration. Motility and velocity of sperms were also measured using non-treated rats. At 0.3 mg DA-125/kg, spermatids per 1g testis and daily sperm production rate per 1g testis were significantly decreased, when compared with those of control group. Several types of abnormal sperms, such as no head, pin head, double head, hook at wrong angle, no tail, and small sperm, were found in both treated and control groups at a low frequency. Serum testosterone concentration at 0.3 mg DA-125/kg was close to the control value. Sperm motility and velocity measured with non-treated rats were in a good agreement with the results of other investigators. In our study established spermatotoxicity test methods can be used as a tool not only for the close examination of the cause of drug- or chemical-induced infertility, but also for the effective evaluation of reproductive toxicity.

• Biomolecules & Therapeutics
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• v.4 no.4
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• pp.354-363
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• 1996

This study was conducted to investigate the repeated dose toxicity of DA-9601, an antiulcer agent of Artemisia app. extract, in rats. DA-9601 was administered orally once a day for 4 weeks to 10 males and 10 females per group at doses of 0(vehicle control), 125, 500 or 2000 mg/kg/day. Throughout the study, no treatment-related deaths and clinical signs were observed. In female rats receiving 125 mg/kg of DA-9601, water consumption increased slightly on day 4, 11 and 25. Hematological examination showed a decrease of MCV and an increase of PLT in male rats at the doses of 500 and 2000 mg/kg groups. Blood biochemistry revealed slight decreases of cholesterol, BUN and Na in male rats and decreases of total bilirubin and creatinine and slight increases of globulin and Cl in female rats. The organ weights at the end of 4 weeks showed slight changes in some organs of treated groups. But, all these changes were not considered to be of toxicological importance, because they did not show dose-response relationship and relevance to gross and microscopic findings. Histopathologically, abnormal treatment-related changes were not observed in any organ and target organs were not detected. On the basis of these results, the NOAEL(no-observed-adverse-effect level) of DA-9601 was estimated to be more than 2000 mg/kg/day under the conditions tested.