[Toxicological studies on (2''R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic. Its acute toxicity in beagle dogs].
(2"R)-4'-O-Tetrahydropyranyladriamycin (THP), a new antitumor antibiotic of anthracycline derivative, was given intravenously to male and female Beagle dogs, followed by observations for 2 weeks. The doses were 0.125, 0.25, 0.5 and 1.0 mg/kg. Observations were performed on mortality, clinical signs, body weight and temperature, food and water consumption, ECG, ophthalmoscopy, testicular measurement, hematology, serum biochemistry, urinalysis, autopsy, histopathology and electron microscopy. The results were as follows. All animals of 1 mg/kg-treated group died but there were no deaths in other groups. All the levels of doses caused vomiting and diarrhea. Furthermore, the highest dose caused bloody diarrhea and decreases in food consumption, motility and body weight, followed by death. These effects may be related to histopathological changes in mucosa of digestive tract. Some changes in water consumption, urine volume and renal histopathology were sporadically observed after treatment, but they were not treatment-related. These results suggest that a treatment with THP does not significantly cause renal disturbance. There were no treatment-related changes in body temperature, ophthalmoscopical observation and testicular measurement. THP produced flattening of T wave and prolongation of QRS interval only at high doses of more than 0.5 mg/kg for males and of 1 mg/kg for females but did not cause any histopathological or electron microscopical changes in hearts. It seems that the abnormalities caused by THP in ECG traces are due to the deterioration of general conditions rather than the direct effect on heart. High doses produce the significant changes in platelet, WBC, Hb, Neutro. (Seg.), Mono., Hb, RBC and Lymph. and further regressive changes in thymus, spleen and bone marrow. These results suggest that THP causes some effects on hemopoietic tissues. The sporadic changes in serum biochemistry and urinalysis were neither related to the treatment nor to the changes in organ weight, autopsy, histopathology and electron microscopy. Therefore, it is likely that THP does not cause toxicological effect on the other tissues and organs except hemopoietic tissues.
M
M
Kurebe
M
M
Yokota
H
H
Watanabe
H
H
Kawaoto
H
H
Suzuki
M
M
Seki
H
H
Hayasaka
N
N
Nakamura
D000818:Animals; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D012737:Sex Factors
D004317:Doxorubicin; C027260:pirarubicin