pirarubicin and Body-Weight

In the preclinical study of a new combination therapy for gastric cancer, dFTP, consisting of doxifluridine (5'-DFUR), pirarubicin (THP) and cisplatin (DDP) as a modification of conventional FAP regimen (5-fluorouracil+Adriamycin+DDP), we compared antitumor and toxic effects of two sequential treatment schedules, single injection of DDP before or after 4 daily administrations of 5'-DFUR, on 5 strains of human gastric cancer bearing nude mice. Results indicated that both schedules of the dFTP regimen had potent antitumor effects. There was no significant difference between them. On the other hand, in terms of the host toxicity as observed by body weight loss, the post-DDP schedule was significantly less toxic than pre-DDP. These results suggest that dFTP regimen (post-DDP schedule) may be useful for clinical treatment of gastric cancers.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cisplatin; Doxorubicin; Drug Administration Schedule; Female; Floxuridine; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Stomach Neoplasms

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

Topics: Animals; Antibiotics, Antineoplastic; Blood Chemical Analysis; Body Weight; Bone Marrow; Dogs; Doxorubicin; Drinking; Eating; Electrocardiography; Eye; Female; Hematologic Tests; Injections, Intravenous; Male; Myocardium; Organ Size; Testis

(2"R)-4'-O-Tetrahydropyranyladriamycin X HCl (THP), a new anthracycline antitumor antibiotic, was administered to Sprague-Dawley rats intraperitoneally for 13 weeks. In rats receiving 0.4 mg/kg/day, piloerection, emaciation, loose feces and thickening of the injection site were evident, and 7 males and 2 females died after week 12. Inferior body weight gain was observed in both sexes starting week 4 approximately 6. The food consumption also decreased. Hematological examination revealed lower counts of total leucocyte and lymphocyte. At termination there were lower spleen, thymus and testes weights, thickening of the walls of the intestine and stomach, gastric ulceration, presence of ascitic fluid, and congestion and thickening at the injection site. Decreases in the lymphocyte populations of the thymus, spleen and lymph nodes were observed microscopically. A decrease in the number of hematopoietic cells in the bone marrow and a degeneration of the germinal epithelium in the testes were also seen, as were gastrointestinal disturbances. These treatment-related effects were mainly confined to rats receiving 0.4 mg/kg/day and to a lesser extent, to rats receiving 0.1 mg/kg/day. The effects on rats receiving 0.025 mg/kg/day were only at the microscopic level. No rats receiving 0.006 mg/kg/day were toxicologically affected.

Topics: Animals; Antibiotics, Antineoplastic; Blood Chemical Analysis; Body Weight; Bone Marrow Cells; Doxorubicin; Drinking; Eating; Female; Hematologic Tests; Injections, Intraperitoneal; Male; Organ Size; Rats; Rats, Inbred Strains

Topics: Animals; Antibiotics, Antineoplastic; Blood Chemical Analysis; Body Weight; Bone Marrow; Cholinesterases; Dogs; Doxorubicin; Drinking; Eating; Electrocardiography; Hematologic Tests; Male; Organ Size; Testis; Urine

(2"R)-4'-O-Tetrahydropyranyladriamycin X HCl (THP), a new anthracycline antitumor antibiotic, was administered to Sprague-Dawley rats (each group 20 rats) intraperitoneally at dosages of 0.001, 0.008, 0.06 and 0.3 mg/kg/day for 53 weeks. Piloerection, loose feces or perianal staining and thin or emaciated build were observed from week 12 in rats receiving 0.06 or 0.3 mg/kg/day. All rats receiving 0.3 mg/kg/day and 3 males and 1 female receiving 0.06 mg/kg/day died or were prematurely sacrificed in the period from weeks 13 to 44. The overall food consumption and body weight gain of both sexes receiving 0.06 or 0.3 mg/kg/day were lower than those of the controls. Hematological examination showed low leucocyte counts, disturbance in neutrophil and lymphocyte number and low erythrocytic characteristics in animals receiving 0.06 or 0.3 mg/kg/day. At necropsy, macroscopic changes were found at the injection site, throughout the gastrointestinal tract and in the male reproductive system in rats receiving 0.06 or 0.3 mg/kg/day. Microscopic examination revealed decrease in the small lymphocyte population in the hematopoietic and lymphoid system in rats receiving 0.008 to 0.3 mg/kg/day. Degeneration of the germinal epithelium of the subcapsular tubules of the testes, gastric ulceration, epithelial adnexal atrophy of the skin and chronic cellulitis and necrosis at the injection sites were also observed. No rats receiving 0.001 mg/kg/day were affected in these respects.

Topics: Animals; Antibiotics, Antineoplastic; Blood Chemical Analysis; Body Weight; Doxorubicin; Drinking; Eating; Eye; Female; Hematologic Tests; Injections, Intraperitoneal; Liver; Male; Organ Size; Rats; Rats, Inbred Strains; Spleen; Urine

Topics: Animals; Antibiotics, Antineoplastic; Body Weight; Bone Marrow; Dogs; Doxorubicin; Drinking; Eating; Electrocardiography; Female; Humans; Injections, Intravenous; Kidney; Liver; Male; Organ Size; Testis

The effect of a new antitumor antibiotic on the fertility was studied using SD rats. (2"R)-4'-O-Tetrahydropyranyladriamycin (THP) was administered to each rat at 0.01, 0.03 or 0.1 mg/kg daily. Males were given the drug intravenously for 63 days prior to mating and during the mating period; females were given the drug intravenously from 14 days prior to mating until day 7 of pregnancy. All the pregnant rats were sacrificed on day 20 of pregnancy, followed by external, visceral and skeletal observations of their fetuses. Results were summarized as follows. THP, at 0.1 mg/kg, suppressed body weight gain in females during the late period of pregnancy but did not affect body weight gain in males. THP, at 0.1 mg/kg, increased the numbers of dead fetuses and of resorptions. It caused no external, visceral or skeletal anomalies at any dose levels. The results suggest that, in rats, the maximum "no effect" dose of THP is 0.03 mg/kg/day intravenously regarding fertility and fetal development.

Topics: Animals; Antibiotics, Antineoplastic; Body Weight; Doxorubicin; Female; Fertility; Fetus; Injections, Intravenous; Male; Pregnancy; Rats; Rats, Inbred Strains

This paper describes the embryotoxicity and teratogenic effects of (2"R)-4'-O-Tetrahydropyranyladriamycin (THP). The drug was administered intravenously to female rats at 0.01, 0.03, 0.1 or 0.3 mg/kg daily from day 7 to day 17 of pregnancy and to female rabbits at 0.01, 0.05 or 0.1 mg/kg daily from day 6 to day 18 of pregnancy. Results were summarized as follows. Rats THP, at the highest dose of 0.3 mg/kg, decreased body weight gains of pregnant females. This dose caused a decrease in body weights of fetuses, tendencies to increase the rate of death of fetuses or of resorption, an increase in the number of lumbar vertebrae and a delayed ossification of forelimbs of fetuses. Other parameters were not affected by THP at any dose levels. At any dose levels, THP did not produce external, visceral or skeletal malformations in the offspring (F1), nor did it affect the development, physiological functions, behavior, mating, fertility or pregnancy of the offspring. However, at the highest dose level, THP decreased the weight of testes of the offspring. The results suggest that the maximum "no effect" dose level of THP to pregnant females and offspring is 0.1 mg/kg/day intravenously. Rabbits The highest dose of THP, 0.1 mg/kg, decreased the consumption of food and water by pregnant females, but at any dose levels, it did not affect their body weight gain. THP did not cause teratological effects such as external malformation or visceral and skeletal anomalies in the fetuses at any dose levels tested. The results suggest that the maximum "no effect" dose of THP is 0.05 mg/kg/day intravenously to pregnant females and above 0.1 mg/kg/day intravenously to fetuses.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Antibiotics, Antineoplastic; Body Weight; Doxorubicin; Drinking; Eating; Embryonic and Fetal Development; Female; Fetus; Injections, Intravenous; Male; Organ Size; Pregnancy; Rabbits; Rats; Rats, Inbred Strains; Reproduction

New Zealand White rabbits were treated with (2"R)-4'-O-tetrahydropyranyladriamycin-HCl (THP), a new antitumor antibiotic, by an intravenous bolus injection at a dose of 1, 2 or 4 mg/kg. The peripheral leucocyte counts decreased markedly at doses of 2 and 4 mg/kg 1 to 7 days after injection, and the lymphocytes and neutrophils were affected. The nucleated cell count decreased in the bone marrow. Especially 3 days after injection, remarkable reductions of erythroids and immatured myelocytes were observed, with a subsequent rise of the matured myelocytes ratio in bone marrow cell constituents. These changes resulted in a marked increase of M/E ratio. Doxorubicin also showed an inhibitory effect on the bone marrow function of rabbits but the effect was slightly lower than THP. These changes of bone marrow cells reverted 7 days after injection and the recovery of the reduced peripheral leucocyte was also observed 14 days after injection. Therefore, it can be concluded that THP showed suppressive but reversible effects on the bone marrow function of rabbits.

Topics: Animals; Antibiotics, Antineoplastic; Blood Chemical Analysis; Body Weight; Bone Marrow; Bone Marrow Cells; Cell Count; Doxorubicin; Eating; Hematologic Tests; Injections, Intravenous; Male; Rabbits

Cardiovascular effects of (2''R)-4'-O-tetrahydropylanyladriamycin X HCl (THP) and doxorubicin (adriamycin, ADM) were studied in hamsters. In experiments to observe acute effects, THP was administered intravenously at a dose of 12.5, 25.0 or 50.0 mg/kg, and ADM at 1.56, 3.13 or 6.25 mg/kg was given to different subjects. The THP caused slight ECG alterations at a dose of 12.5 mg/kg. At a dose of 25.0 mg/kg or 50.0 mg/kg, THP caused moderate to remarkable alterations in ECG like a widening of PR and PRc interval, A-V block, ST segment depression and T wave flattening. The ADM caused moderate to remarkable alterations in ECG at a dose of 3.13 mg/kg or 6.25 mg/kg, including arrhythmia, bradycardia, A-V block, ST segment changes and T wave flattening. These changes caused by THP and ADM recovered within 5 approximately 10 minutes after injection. Alterations in the ultrastructure of the myocardium caused by THP at a dose of 50.0 mg/kg included some cells with slight changes like swelling of mitochondria, focal intracellular edema, and enlargement of myofibrils. The ADM, at a dose of 3.13 mg/kg, induced severer swelling of mitochondria than THP, dilatation of sarcoplasmic reticulum, intracellular edema, and disorganization of myofilaments. At a dose of 6.25 mg/kg of ADM, these changes became more pronounced. In experiments to observe subacute effects, hamsters were treated with THP or ADM by daily intraperitoneal injections for 15 consecutive days, and then allowed to be recovered for 15 days. Dose levels of THP or ADM were 0.125, 0.25, 0.5 and 1.0 mg/kg. General toxicity, ECG, hematological and blood biochemical analysis, and electron microscopic examination were studied. In the ECG study, THP-treated hamsters showed a reversible elevation of R wave amplitude at a daily dose of 0.5 mg/kg. Widening of PR and PRc interval, elevation of R and S wave amplitude, and reduction of T wave amplitude were observed at a daily dose of 1.0 mg/kg of THP. Hamsters treated with ADM showed increase of heart rate, reduction of T wave amplitude, and shortening of PR and PRc interval at a daily dose of 0.5 mg/kg. Severe changes were observed at a daily dose of 1.0 mg/kg of ADM including an increase of heart rate, elevation of R wave amplitude, reduction of S and T wave amplitude, and shortening of QT interval. The electron microscopic examination revealed that THP-treated hamsters showed separation of intercalated discs, formation of myelin structure, and dilatation of T-tubules

Topics: Animals; Antibiotics, Antineoplastic; Blood Chemical Analysis; Body Weight; Cricetinae; Dose-Response Relationship, Drug; Doxorubicin; Electrocardiography; Heart; Heart Rate; Hematologic Tests; Injections, Intravenous; Male; Microscopy, Electron; Myocardium

(2''R)-4'-O-Tetrahydropyranyladriamycin-HCl (THP), a new antitumor antibiotic, was intravenously injected to New Zealand White rabbits at a dose of 2.5 mg/kg every 2 weeks for 6 weeks (3 courses) or at a dose of 0.5 mg/kg/day daily for the first 5 days of a 2-week course for 6 weeks (3 courses). The total dose was 7.5 mg/kg in both dosing schedules. The peripheral leucocyte and erythrocyte counts decreased. The leucocyte count decreased to 57% of the initial count on Day 3 in the first course and then increased gradually. The decrease was smaller in the divided dosing schedule than the single dosing. The nucleated cells, especially immatured myelocytes and erythroids reduced remarkably. Subsequently the matured myelocyte ratio in bone marrow cell constituents increased and the M/E ratio increased. These changes were observed on Day 3 and reverted by Day 9 in each course. The divided dosing schedule resulted in a higher nadir. All the changes in the peripheral blood and the bone marrow reverted even after the 3 course-treatment.

Topics: Animals; Antibiotics, Antineoplastic; Blood Chemical Analysis; Body Weight; Bone Marrow; Bone Marrow Cells; Cell Count; Doxorubicin; Eating; Hematologic Tests; Injections, Intravenous; Male; Rabbits

A statistically significant circadian rhythm in tolerance of 226 male B6D2F1 mice synchronized with LD 12:12 for 4'-O-tetrahydropyranyl-adriamycin (THP) was demonstrated. Four intravenous dosages (18, 25, 32 and 40 mg/kg) and six different dosing times (3, 7, 10, 14, 19 and 23 hr after light onset-HALO) were compared. Survival rate, body weight loss and leukopenia depended on both the dose and time of injection. The overall survival rate varied between 83% (light-rest span) and 56% (dark-activity span) (chi2 = 17; d.f. = 2; P less than 0.001). Maximal body weight loss occurred 4-5 days after drug injection. Total leukocyte counts were determined on these days. Both body weight loss and leukopenia were reduced by approximately 100% in those mice injected in their late rest span (7-10 HALO) as compared to those treated in the middle of their activity span (19 HALO). Circadian rhythms in day-60 survival rate, body weight loss and leukopenia were statistically validated by cosinor analysis, with estimated peak times (acrophases) occurring respectively at 7:30, 9:20 and 8:40 HALO. Minor cardiac lesions consisting of diffuse vacuolization and loss of muscular striation were observed in histologic sections from 3/32 hearts (16 controls, 16 treated). All three corresponded to THP given at 19 (2/2 mice) or 23 HALO (1/4 mice). Thus lethal, hematologic and possibly cardiac tolerance for THP were largely optimized by administering the drug to mice in their late span (7-10 HALO).

Topics: Animals; Body Weight; Circadian Rhythm; Dose-Response Relationship, Drug; Doxorubicin; Drug Tolerance; Leukocyte Count; Leukopenia; Male; Mice; Mice, Inbred Strains; Myocardium