• Toxicological Research
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• 제8권2호
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• pp.205-216
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• 1992

cis-Malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II)(SKI 2053R), an antitumor platinum complex, was selected for clinical evaluation on the basis of its experimental antitumor and toxicologic profiles in preclinical studies. These studies were performed to obtain information on its toxic signs, orgnas which are mainly affected, and to estimate its lethality in mice and rats given SKI 2053R through two routes of administration. In male and female rats given a single intragastrical dose of SKI 2053R, we estimated that $LD_{50}$ values were over 3.00g/kg, respectively. In male and female mice given a signle intragastrical dose of SKI 2053R, we estimated that $LD_{50}$ values were 2.44g/kg and 1.59g/kg, respectively, In a single intraperitoneal dose of SKI 2053R, we determined that $LD_{50}$ values of male and female rats were 227mg/kg and 182mg/kg, and those of male and female mice were 198mg/kg and 207mg/kg, respectively. In gross and histopathological examinations on dead animals, we found that kidney and liver were mainly affected.

• Toxicological Research
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• 제8권2호
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• pp.235-253
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• 1992

A subacute toxicity study of cis-Malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II)(SKI 2053R) was carried out to obtain information on its toxicological profiles, and to determine the maximum tolerated dose in beagle dogs. Four groups of beagle dogs (2M and 2F per group, 0,0.5,1.0,2.0mg/kg/day)were given 15 i.v. injections of SKI 2053R. In order to compare the toxic effects of SKI 2053R with those of cisplatin, one group was treated with cisplatin(0.7mg/kg/day)according to the same treatment schedule. The dosing schedule was divided into 3 courses of 5 consecutive days with 23-day dose-free intervals between each course. After completion of the treatments, remaining dogs were necropsied under established guidelines. Three of four dogs in the high dose group and one of four dogs in the middle dose group treated with SKI 2053R died of hypovolemic shock secondary to hemorrhagic and ulcerative enterocolitis. No toxicity-related mortality occurred in the low dose group of SKI 2053R. No survivor was observed in the group of cisplatin. Clinical signs including vomiting, diarrhea, anorexia and loss body weight were apparent in dogs given either cisplatin or high and middle doses of SKI 2053R. Severe thrombocytopenia and leukocytopenia were observed in the high dose group of SKI 2053R and cisplatin-treatment group, while toxicities as bone marrow suppression were reversible. The significant elevation of serum ALP values in group of SKI 2053R(2.0 mg/kg/day and 1.0mg/kg/day) and cisplatin(0.7mg/kg/day)was observed. Slight proteinuria waa observed in high and middle dose level groups of SKI 2053R. In histopathological examinations, pathological alterations of liver, kidney and spleen were noted dose-dependantly in dogs treated with SKI 2053R, and there was no overt sign of toxicity in low dose group of SKI 2053R. Compared to SKI 2053R, more severe durg-related toxicities occurred in dogs treated with cisplatin. It waw estimated that maximum tolerated dose of SKI 2053R in this treatment schedule was 0.5~0.7mg/kg/day. In conclusion, overall toxic potential of SKI 2053R was approximately 3 times lower than that of cisplatin with respect of lethality.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1993년도 제2회 신약개발 연구발표회 초록집
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• pp.73-73
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• 1993

As part of a research program to develope 3rd generation anti tumor platinum complexes, a series of platinum complexes which have 4, 5-bis-(aminomethyl)- 1, 3-dioxolane derivatives as bidenate amine ligands, represented by the general structual formula was prepared. The R$_1$ and/or R$_2$ substituents in this series of platinum complexes can be hydrogen. alkyl, of jointly formed cyclohexane. Two Xs can be a bidenate leaving ligand such as 1, 1-cyclobutanedicarboxylate, malonate, dimethylmalonate, ethylmalonate, glycolate, L-lactate, or N-methyliminodiacetate. From based on the pharmacological and toxicological studies, we have chosen SKI 2053R, cis-malonato[(4R, 5R)-4, 5-bis(aminomethyl)-2-isopropyl-1, 3-dioxolane] platinum(II) complex (NSC D644591) as a candidate for clinical evaluation. The antitumor activity of a new anti tumor platinum complex, cis-malonato [(4R, 5R)-4, 5-bis(aminomethyl)-2-isopropyl-1, 3-dioxolane] platinum(II) (SKI 2053R, NSC D644591), was compared with those of cisplatin and carboplatin using murine tumors. We evaluated three platinum complexes against L1210/CPR, a subline of L1210 leukemia resistant to cisplatin for their abilities to overcome tumor resistance to cisplatin. The in vitro cytotoxicity of SKI 2053R to L1210 cell line was 2.5-fold less potent thann that of cisplatin, and was 10-fold more cytotoxic than that of carboplatin. SKI 2053R retained similar cytotoxic effect and anti tumor activity to L1210/CPR cell line, like the cytotoxicity of SKI 2053R to L1210 cell line, while either cisplatin or carboplatin had not property to overcome the acquired cisplatin-resistance. SKI 2053R exhibited greater or comparable antitumor activity than cisplatin or carboplatin in murine tumor models.

• Toxicological Research
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• 제8권2호
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• pp.217-233
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• 1992

This study was performed to determine the toxic effects of graded dose levels of SKI 2053R after repeated administration. Three groups of Sprague-Dawley rats(10M and 10F per group) were given a total of 25 i.v. injections of SKI 2053R (1.50,3.75,9.38mg/kg/day). In order to compare the toxic effects of SKI 2053R with those of cisplatin, one group of Sprague-Dawley rats (10M and 10F per group) were given a total of 25 i.v.injections of cisplatin (1.70mg/kg/day). The dosing schedule was divided into five courses of 5 consecutive days with 16-day dose-free intervals between each course. No drug-related toxicity occurred in low dose level group (1.50mg/kg/day) of SKI2053R. From the results of hematological examination, peripheral WBC counts, RBC counts and hemoglobin of high dose level group(9.38mg/kg/day)of SKI 2053R were significantly lower than those of no-treated group. Other toxicities including reduced final body weight, proteinuria and hematuria were observed in high dose level group of SKI 2053R. But, no change was detected in serum biochemical values of SKI 2053R treated groups. All of the rats in cisplatin treated group were died between 3 and 13 weeks, while rats treated with SKI2053R survived to the end except one rat of middle dose level group(3.75mg/kg/day). In histopathological examinations, rats that received cisplatin manifested severe tubular damage in kidney and hemosiderosis in spleen, but no critical pathological lesion was observed in rats of other groups. Considering the results of this study, it was concluded that non-toxic dose of SKI 2053R in this treatment schedule was estimated to be 3.75 mg/kg/day and the maximum tolerated dose was to be higher than 9.38mg/kg/day. The toxic profiles fo SKI 2053R were different from those of cisplatin, and its toxicity was considerably lower than that of cisplatin.

• Toxicological Research
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• 제8권2호
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• pp.255-263
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• 1992

SKI 2053R and SKI 2053R-human serum albumin(HSA) mixture were examined for their antigenicity in Hartley guinea pigs as well as C57BL/6 mice in comparison with distilled water (DW), HSA and DW-HSA conjugate. Several antigenicity tests, including acitive systemic anaphylaxis(ASA), passive systemic anaphylaxis (PSA), passive cutaneous anaphylaxis (PCA) and indirect hamagglutination test (IHA), were performed according to the Established Regulations of National Institute of Safety Research. The results were as follows: 1. When guinea pigs were sensitized with SKI2053R or SKI2053R-HSA emulsified with complete Freund's adjuvant(CFA), these animals showed negative reactions in ASA and PSA. 2.No blue spot was observed on the back skin of guinea pigs in the PCA test. 3. Sera from guinea pigs revealed a negative reaction in IHA. 4.Guinea pigs were sensitized by HSA emulsified with CFA as a positive control, and these animals showed positive reactions in ASA, PSA, PCA, and IHA. As shown above, SKI2053R was considered to possess neither antigenic, nor haptenic properties, and confirmed not to have the haemagglutinating activity.

• Biomolecules & Therapeutics
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• 제7권3호
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• pp.292-299
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• 1999

SKI 2053 R, cis-Malonato [(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum(II), is a newly developed antitumor platinum complex derived from cisplatin. Preclinical studies suggest that it may have greater antitumor activity and lower toxicity than cisplatin. Effects of test agent on general toxicity of does and embryonic development of Fl fetuses were investigated in rabbits. Sixty eight New Zealand white rabbits were distributed among three treated groups and a control group. SKI 2053R was administered intravenously to pregnant rabbits from days 6 to 18 of gestation at dose levels of 0, 0.67, 2.0, or 6.0 mg/kg/day. The pregnant does were subjected to the caesarean section on day 28 of gestation. No treatment-related changes in clinical signs, body weight, food consumption, and necropsy findings were observed in all groups. Fl fetuses showed no changes related to the treatment of SKI 2053R, except that an increase in the incidence of skeletal variations were observed at 6.0 mg/kg. There were no signs of material toxicity or embryotoxicity at 0.67 and 2.0 mg/kg. The results show that the administration of 6.0 mg/kg SKI 2053R induces skeletal variations in fetuses and that the no observed adverse effect levels(NOAELS) of SKI 2053R are considered to be over 6.0 mg/kg for does and 2.0 mg/kg for Fl fetuses in rabbits.