aclarubicin and Body-Weight

Effects of anthracycline type antitumor agents (aclarubicin, ACL; daunorubicin, DAU; doxorubicin, DOX; epirubicin, EPI; pirarubicin, PIR) on the acute toxicity to mouse, rat liver microsomal lipid peroxidation and mitochondrial functions in vitro were studied. ACL showed the least production of liver microsomal lipid peroxidation in all tested anthracyclines in the increasing order of PIR, DOX, DAU and EPI. The increase of production of lipid peroxidation induced by these drugs correlated well with the decrease in body weight of mice administered i.p. at 20 mg/kg and 50% lethal dose of these drugs. On the effect of mitochondrial function, all drugs tested decreased the oxygen uptake of state 3 and the level of respiratory control index. ACL showed the most severe inhibition of these functions in all drugs. These observations suggest that the degree of microsomal lipid peroxidation induced with the anthracycline drugs was related to the development of the drug acute toxicity.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Body Weight; Daunorubicin; Doxorubicin; Epirubicin; Lipid Peroxidation; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Mitochondria, Liver; Rats; Rats, Inbred Strains

A new dosage form (ACR-CH), a suspension of small activated carbon particles adsorbing aclarubicin, was studied for its toxicity and histopathological effects on organs in mice. The 50% lethal subcutaneous dose of ACR-CH was 83.5 mg/kg, a value 2.42 times that (34.5 mg/kg) of the aclarubicin aqueous solution. The duration of the toxic effects of ACR-CH was prolonged compared with that of the aclarubicin aqueous solution. On autopsy there was no remarkable difference in macroscopic and microscopic examinations between the two dosage forms.

Topics: Aclarubicin; Animals; Body Weight; Carbon; Female; Intestines; Lethal Dose 50; Mice; Skin; Spleen; Suspensions; Thymus Gland

The anti-cancer drug Aclacinomycin A (ACM) was able to inhibit the humoral immune response of mice against sheep red blood cells. This could be demonstrated in the formation of antibody secreting cells (PFC) and serum antibody titers, when ACM was administered either together with the antigen or three days after antigen application. Cellular immunity was not affected by the drug. In two murine Graft-vs-Host (GvH) disease models leading to two different B cell dependent auto-immune diseases (immune complex glomerulonephritis and immune hemolytic anemia) a protective effect of ACM was observed when it was administered at the time of the graft. The application of ACM in the induction phase mitigated the development of glomerulonephritis and prevented animals from dying due to hemolytic anemia. Only a slight therapeutical effect was observed when ACM was given after the appearance of clinical symptoms. In a T cell induced auto-immune disease (experimental allergic encephalomyelitis (EAE], ACM had no discernible effect on the course of the disease. It seems that the therapeutic effects of ACM on GvH-diseases are mediated via suppression of B-lymphocytes.

Topics: Aclarubicin; Anemia, Hemolytic; Animals; Antibiotics, Antineoplastic; Antibody Formation; Autoimmune Diseases; Body Weight; Encephalomyelitis, Autoimmune, Experimental; Female; Glomerulonephritis; Immunity, Cellular; Immunosuppressive Agents; Leukocyte Count; Male; Mice; Mice, Inbred Strains; Naphthacenes; Rats; Rats, Inbred Lew

Adriamycin (ADM) is a very effective antimitotic agent but its use is limited by its cardiotoxicity. New anthracycline drugs such as aclacinomycin A (ACMA) have been developed and have to be compared with ADM after chronic experimental intoxication. Three groups of randomised rats were compared: the ADM group receiving 2 mg/kg/week X 13 by intraperitoneal injection; the ACMA group receiving 4 mg/kg/week X 13 and a control group: 7 rats. The rats were autopsied at the 20th week. The heart was stopped in diastole and fixed by aortic retroinfusion of glutaraldehide for electronic microscopy (EM). In the ADM group, mean weight fell from the 4th week and mortality was 11/16 at 20 weeks. Voluminous haemorrhagic ascites was associated with peritoneal fibrosis in 12/16. Cardiac failure was observed in 4 cases but on light microscopy (LM) myofibril degeneration was constant and focal without sarcoplasmic reticulum or mitochondrial changes on EM. In the ACMA group the loss of weight occurred at 10 weeks and mortality due to toxicity was nil. There was no cardiac failure; myocytolysis was absent on LM and slight in 4/13 cases on EM with a moderate dilatation of the sarcoplasmic recticulum and presence of numerous residual bodies in the striated skeletal fibres in 5/15 cases. In this study, the ACMA had very little cardio and general toxicity in comparison with ADM. The technique of fixing the heart by retrograde infusion prevents, as far as possible, artefacts on EM affecting mainly the mitochondria.

Topics: Aclarubicin; Animals; Body Weight; Cardiomyopathies; Doxorubicin; Male; Myocardium; Naphthacenes; Random Allocation; Rats

New antitumor anthracycline antibiotic, aclacinomycin A was given to dd-mice and Wistar rats for acute toxicity study. The LD50 values were 29 approximately 39 mg/kg (i.v., i.p. and s.c.) and 62 approximately 69 mg/kg (p.o.) in mice, and 18 approximately 28 mg/kg (i.v., i.p. and s.c.) and 58 approximately 59 mg/kg (p.o.) in rats, respectively, which were calculated by mortality rate during a 14 day observation period. Depression of spontaneous activity, anorexia, diarrhea and slight alopecia were observed. Autopsy findings in animals killed by drug included atrophy of the thymus and spleen, and hyperemia and hemorrhage in the stomach and intestines. But no remarkable change was found in animals which survived through the observation period. Mongrel dogs were given the drug intravenously at 3, 5, 7.5, 10 and 15 mg/kg, respectively. All dogs (3/3) in the three higher dose groups and 1/3 dog in 5 mg/kg dose group died within day 0 approximately 5. Others survived more than 27 days. Depression of spontaneous activity and anorexia were found from 30 minutes to 2 hours after administration, followed by vomiting and diarrhea. Increase of GOT, GPT and LDH and decrease of WBC count were detected in dogs which died. Hyperemia and hemorrhage of the lungs, stomach and intestine were found among the groups given higher doses, whereas no significant changes were recognized among the two lower dose groups.

Topics: Aclarubicin; Animals; Blood Chemical Analysis; Body Weight; Dogs; Female; Hematologic Tests; Lethal Dose 50; Male; Mice; Naphthacenes; Rats; Time Factors

Wistar rats, both male and female, were treated with aclacinomycin A at 4 dosage levels (0.375, 0.75, 1.5 and 3.0 mg/kg/day) by daily intraperitoneal injection for 30 days. Several rats died in the two higher dose groups (1.5 mg/kg/day: male 2/8 and 3.0 mg/kg: male 8/8, female 8/8. Piloerection, anorexia, depression of spontaneous activity, diarrhea and slight incontinence were observed in rats in 3.0 mg/kg/day dose group. Body weight gain decreased after day 3 in rats receiving 1.5 and 3.0 mg/kg/day. A significant decrease in the total WBC count and a slight decrease in RBC count were observed in animals of 1.5 mg/kg/day dose group which were survived for 30 days. Autopsy findings demonstrated atrophy of the thymus and spleen, and hyperemia and hemorrhage in the intestine. The atrophy of the thymus and decreased hematopoiesis in the bone marrow were histologically noted in the two highest dose groups. No cardiotoxicity was observed.

Topics: Aclarubicin; Animals; Blood Chemical Analysis; Body Weight; Drinking; Eating; Electrocardiography; Female; Hematologic Tests; Male; Naphthacenes; Organ Size; Rats

Male golden hamsters were treated with aclacinomycin A or adrianmycin by daily intraperitoneal injections for 15 consecutive days, and then allowed to be recovered for 15 days. Dose levels of aclacinomycin A and adriamycin were 1.5, 2.0 and 3.0 mg/kg, and 0.17 and 0.5 mg/kg, respectively. General toxicity, electrocardiogram (ECG), blood biochemical analysis and light microscopic and electron microscopic examinations were studied. The two drugs produced body weight loss at a dose of 3.0 mg/kg and 0.5 mg/kg, respectively. Death occurred in hamsters treated with aclacinomycin A at the highest dose (4/6 animals). In ECG study, aclacinomycin A-treated hamsters showed reversible QRS duration prolongation and T wave flattening at a dose of 1.5 or 2.0 mg/kg. Adriamycin-treated animals at a dose of 0.5 mg/kg showed R wave amplitude elevation during dosing period, and PR interval prolongation, R wave amplitude elevation and S wave amplitude reduction during recovery period. Blood biochemical analysis demonstrated reversible elevation of lactate dehydrogenase and alpha-hydroxybutyrate dehydrogenase activities in aclacinomycin A-treated hamsters at a dose of 2.0 mg/kg, and an increase in lipoperoxide in adriamycin-treated animals at a dose of 0.5 mg/kg during dosing period. Histologically, both drugs produced separation of myofilaments, swelling of mitochondria, dilation of sarcoplasmic reticulums and decreases in glycogen and lipid particles in myocardium. But aclacinomycin A-treated hamsters rarely showed these alterations after recovery period, whereas adriamycin-treated animals showed separation and necrosis of myofilaments, fibrosis of muscle fibers and formation of myelin figure even after recovery period. These results suggested that cardiotoxicity caused by aclacinomycin A was reversible and milder than that by adriamycin.

Topics: Aclarubicin; Animals; Anti-Bacterial Agents; Blood Chemical Analysis; Body Weight; Cricetinae; Doxorubicin; Electrocardiography; Heart; Injections, Intraperitoneal; Male; Myocardium; Naphthacenes

Subacut e cardiotoxic effect of aclacinomycin A or adriamycin given by daily intraperitoneal injections for 5 days was studied in rats by electrocardiography (ECG), blood biochemical analysis, light microscopy and electron microscopy. Dose levels of aclacinomycin A and adriamycin were 4 and 8 mg/kg, and 2 and 4 mg/kg, respectively. The two drugs caused severe body weight loss at a dose of 8 mg/kg and 4 mg/kg, respectively. Aclacinomycin A-treated rats at a dose of 4 mg/kg showed slight changes in ECG, whereas adriamycin-treated rats at the same dose showed a heart rate decrease, QRS duration and QT interval prolongation and R and S waves amplitude elevation. Blood biochemical changes caused by both drugs at a dose of 4 mg/kg were increased in lipoperoxide and alpha-hydroxybutyrate dehydrogenase activity. Aclacinomycin A gave slight ultrastructural changes in some cardiac cells such as formation of myelin figure and vacuolization in mitochondria. But adriamycin caused remarkable alterations such as degeneration and destruction of mitochondria, vacuolization of sarcoplasm and disappearance of myofilaments, which were often observed near the capillaries and nuclei. These results suggest that the two antibiotics caused cardiotoxicity by a similar mechanism. However, the damage produced by aclacinomycin A was milder than that of adriamycin.

Topics: Aclarubicin; Animals; Anti-Bacterial Agents; Blood Chemical Analysis; Body Weight; Doxorubicin; Electrocardiography; Female; Heart; Heart Rate; Injections, Intraperitoneal; Male; Microscopy; Myocardium; Naphthacenes; Rats

Male and female Wistar rats were treated with aclacinomycin A, a new anthracycline antitumor antibiotic, at 5 dosage levels (0.08, 0.15, 0.3, 0.6 and 1.2 mg/kg/day) by daily intraperitoneal injections for 180 days for a chronic toxicity study. Recovery was also examined for 30 days after completion of the administration. Mortality was as follows: Male 5/24, female 3/24 in 0.6 mg/kg/day dose group and male 19/24, female 8/24 in 1.2 mg/kg/day dose group. Anorexia, depression of spontaneous activity and unformed feces were observed in rats in 0.6 and 1.2 mg/kg/day dose groups after day 90. Body weight gain decreased during the period. No significant change was found in rats receiving the drug at 0.3 and less mg/kg/day all through the observation period. Remarkable decreases in WBC count were noted in rats in the two highest dose groups on day 90. Autopsy findings included atrophy of the thymus and hyperemia and hemorrhage in the gastrointestinal tract and mesenteric lymph node in the animals treated at 0.6 and 1.2 mg/kg/day in the examination on day 90. Histologically, atrophy of the thymus and hyperplasia of the spleen were observed in the higher dose groups on day 90. But no remarkable abnormalities were found in histological examination on day 180. The changes in general symptom and decrease in body weight gain, which were observed during the dosing period in rats in 0.6 mg/kg/day dose group, recovered within 30 days after the drug administration was discontinued but no complete recovery of the WBC count decrease was observed.

Topics: Aclarubicin; Animals; Anti-Bacterial Agents; Blood Chemical Analysis; Body Weight; Drinking; Eating; Female; Hematologic Tests; Injections, Intraperitoneal; Liver; Lung; Male; Myocardium; Naphthacenes; Organ Size; Rats; Spleen

Japan White rabbits were treated with aclacinomycin A, a new anthracycline antitumor antibiotic, at a dose of 6.25 or 25.0 mg/kg by single intravenous, or 12.5 or 50.0 mg/kg by single oral administration, respectively. Beagle dogs were treated at a dose of 3.0 or 6.0 mg/kg by single intravenous injection. In rabbits in higher dose groups, RBC and WBC counts as well as lymphocyte ratio in peripheral blood decreased on day 1. Nucleated cell counts and erythroid elements in bone marrow decreased to raise M/E ratio (Myeloid/Erythroid ratio) on day 3. In a dog given at 6.0 mg/kg, WBC and platelet counts, lymphocyte and neutrocyte per cents in peripheral blood and also nucleated cells, particularly erythroid elements in bone marrow remarkably decreased on day 3 accompanied with an increase in M/E ratio. These changes were almost completely recovered by day 14 in both animals. No abnormalities were found in lower dose groups. Male Wistar rats, treated with the drug at a dose of 1.5 mg/kg by daily intraperitoneal injection for 30 days, showed slight decreases in peripheral WBC and RBC counts and M/E ratio in bone marrow. No change was observed in rats treated at 0.75 mg/kg and less for 30 days.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Body Weight; Bone Marrow; Bone Marrow Cells; Dogs; Eating; Female; Hematologic Tests; Male; Naphthacenes; Rabbits; Rats