PNU-159548, a novel cytotoxic antitumor agent with a low cardiotoxic potential.

PURPOSE: PNU-159548 (4-demethoxy-3'-deamino-3'aziridinyl-4'-methylsulphonyl-daunorubicin), a derivative of the anticancer idarubicin, has a broad spectrum of antitumoral activity in vitro and in vivo attributable to its DNA intercalating and alkylating properties. The present study was conducted to determine the cardiotoxic activity of PNU-159548 relative to doxorubicin in a chronic rat model sensitive to anthracycline-induced cardiomyopathy. METHODS: Young adult male rats were allocated to the following treatment groups: group 1, PNU-159548 vehicle control (colloidal dispersion); group 2, doxorubicin control (saline); groups 3, 4, 5, 6, and 7, PNU-159548 at 0.12, 0.25, 0.50, 0.75, and 1.0 mg/kg, respectively; and group 8, 1.0 mg/kg doxorubicin. Treatments were administered intravenously once weekly for 4 weeks (first sacrifice time) or for 7 weeks (rats killed at weeks 8, 12, 22, 27, or 35). Body weights, organ weights, serum chemistry, hematology, serum troponin-T, and cardiac histopathology were followed throughout the study. RESULTS: Doxorubicin caused irreversible cardiomyopathy evident at week 4 in some rats and progressing in severity in all rats by week 8. There were also marked myelotoxicity, increased liver and kidney weights, testicular atrophy, and about 20% mortality by week 27 in doxorubicin-treated rats. The deaths were attributed to cardiomyopathy and/or nephropathy. PNU-159548 caused a dose-dependent myelotoxicity, with the dose of 0.5 mg/kg per week being equimyelotoxic to 1.0 mg/kg per week doxorubicin. PNU-159548 also caused an increase in liver weight that was reversible and a non-reversible testicular atrophy but, unlike doxorubicin, had no effect on kidney weight. At equimyelotoxic doses, the cardiotoxicity caused by PNU-159548, expressed as the mean total score, was less than one-twentieth of that induced by doxorubicin, and much less than that predicted on the basis of its content of idarubicin, which is in turn markedly less cardiotoxic than doxorubicin. CONCLUSIONS: The novel cytotoxic antitumor derivative, PNU-159548, is significantly less cardiotoxic than doxorubicin at equimyelosuppressive doses. The combination of intercalating and alkylating activities within the same molecule without the cardiotoxic side effects of anthracyclines makes PNU-159548 an excellent candidate for clinical development in oncology.

Protection against doxorubicin-induced cardiotoxicity in weanling rats by dexrazoxane.

PURPOSE: Dexrazoxane (DZR) protects against anthracycline-induced cardiotoxicity in several laboratory animal species and in patients with breast cancer. Encouraging results have also been obtained in a limited number of pediatric oncology patients. We conducted studies to determine the safety and cardioprotective activity of DZR in the doxorubicin (DOX)-treated weanling rat simulating the rapidly growing immature child. METHODS: Male weanling rats and young adult rats, 20 days old and 7 weeks old, respectively, were given 1 mg/kg DOX i.v., either alone or with 20 mg/kg DZR, once weekly for 7 weeks. Rats were sacrificed at weeks 8, 12 or 26 following blood collection for hematology and serum chemistry. Hearts were weighed and examined histologically. RESULTS: DOX, either alone or with DZR, inhibited growth, and body weight remained below that of controls throughout the 26 weeks of study. There were no biologically significant hematologic changes in either the DOX- or DZR + DOX-treated young rats. DOX caused a slight increase in liver and kidney weights relative to body weight and a slight increase in serum cholesterol and triglycerides in the young rats. These effects were ameliorated or delayed by DZR. DOX, either alone or with DZR, caused a marked atrophy of the testes in the young rats which had recovered by week 26. In the mature rats, DOX caused a significant decrease in the WBC 1 week after the last treatment, and the WBC was significantly lower in the rats given DZR + DOX compared to those given DOX alone. There were marked increases in liver and kidney weight, serum cholesterol and triglycerides in the mature rats given DOX alone but not in those given DZR + DOX. There was also a marked testicular atrophy in the mature rats given either DOX or DZR + DOX but, unlike that observed in the young rats, this had not returned to normal by week 26. DOX-induced cardiotoxicity was less severe in the younger rats than in the mature rats but in both age groups, the lesion progressed rapidly until week 12, 5 weeks after the last dose, and remained relatively stable or progressed slightly thereafter. DZR provided significant cardioprotection in both age groups at all time points examined. Moreover, in both age groups, the severity of the cardiomyopathy in the DZR-treated rats was somewhat less at week 26 than it was at week 12. CONCLUSIONS: The results indicate that the pharmacologic effects of DZR, including its ability to protect against cardiotoxicity, are similar in immature and adult male animals treated with DOX.

Anthracyclines.

The genotoxicity and carcinogenicity data from in vitro and in vivo studies conducted during preclinical safety assessment of doxorubicin (DOXO), epirubicin (EPI) and idarubicin (IDA), are reviewed. The genotoxicity assays included a) gene mutation in Salmonella typhimurium with 5 tester strains; b) gene mutation in the V79 mammalian (lung) cell line; c) chromosome aberrations in human lymphocytes cultured in vitro; and d) chromosome aberrations in mouse bone marrow cells after intravenous (i.v.) administration in vivo. The long-term toxicity studies in the rat included a) single dose administration (3 mg/kg DOXO, 3.6 EPI and 0.75 IDA) to female rats of two different age groups, i.e. younger (7 weeks old at dosing) and older (13 weeks old), followed by one-year observation; and b) multiple dose administration to male and female rats (7 weeks old at dosing), consisting of i.v. administration of 0.25, 0.5 and 1 mg/kg DOXO or EPI and 0.06, 0.125 and 0.25 mg/kg IDA, once every 3 weeks for 10 cycles, followed by 18 months of observation. The genotoxicity studies revealed activity in gene mutation assays in bacterial and mammalian cells, and in chromosome aberration assays in human lymphocytes in vitro and in mouse bone marrow in vivo. In the two long-term studies in the rat, only mammary tumors were present. This finding was expected and, according to the literature, can be considered as species specific and not directly compound-related. The lack of tumor induction at the usual target organs for DNA reactive compounds, which are almost the same as those considered as target organs in anthracycline-exposed animals, indicates that the type and the extent of DNA damage precludes stimulation for proliferation and induction of neoplasia. Although an epigenetic mechanism can be hypothesized, support for such a mechanism is lacking.

Overview of toxicological data on rifabutin.

Rifabutin is a wide spectrum antibiotic particularly active on atypical and rifampicin-resistant mycobacteria. Rifabutin is more potent than rifampicin on Mycobacterium tuberculosis in vitro. Its mode of action is characterized by a high intracellular penetration in treated individuals. Clinical trials have proven the therapeutic value of rifabutin especially in AIDS patients with concomitant MAC. The preclinical safety evaluation of this compound included single and repeated dose toxicity studies of up to one year in rodents and non-rodents, reproduction and carcinogenicity studies and mutagenicity tests. During toxicological studies the most significant finding after repeated administration of rifabutin was the presence of multinucleated hepatocytes (MNH) in rats. This is a species specific finding which did not affect the life span of the hepatocytes. As shown in carcinogenicity studies, there was no tendency to further proliferative changes. Another specific histological feature among the species studied was the presence of a lipofuscin-like brown pigment, which was seen in many organs. This is a common finding with amphipilic compounds, such as rifabutin, which bind lipids and proteins, forming membrane-bound complexes. Even in carcinogenicity studies this change did not constitute a stimulus to cell proliferation and did not cause any secondary changes. In rodents, there was a mild hemolytic anemia at doses higher than 10 mg/kg/day. At doses ranging from 160-200 mg/kg/day rifabutin inhibited the functions of the male gonads in rats. This effect was reflected in a reduction of implantations observed in the fertility studies. Doses of 40 mg/kg/day did not induce any embryotoxic effects or changes in reproductive performance.(ABSTRACT TRUNCATED AT 250 WORDS)