Pulmonary toxicity of doxorubicin administered by in situ isolated lung perfusion in dogs.
The possibility of in situ isolated lung perfusion as a means of treating nonresectable pulmonary cancers unresponsive to conventional chemotherapy has been investigated. The present study has examined the biochemical and morphological effects of in situ isolated lung perfusion in dogs with doxorubicin (DOX). A dose related complication was seen in the animals following lung perfusion. Lactate dehydrogenase (LDH) activity in the perfusate increased as dose was increased, indicating tissue damage during the perfusion. Up to 7 days postperfusion, marked changes were seen in the serum protein concentrations although these were independent of doxorubicin concentrations. Serum lactate dehydrogenase showed a dose dependent increase 2 hour and 1 day after the lung perfusion. Plasma angiotensin converting enzyme activities up to 14 days postperfusion suggested that DOX produced pulmonary endothelial cell injury at higher drug doses. Histopathologic examination of the lungs from dogs receiving the highest concentrations of drug indicated that necrosis of arterial endothelia and alveolar epithelia accompanied by periarterial edema, subplural edema and emphysema of the lungs were the probable causes of acute animal mortality. The study has demonstrated that doxorubicin produces dose-dependent damage to the pulmonary tissue. However, the observed injury only appeared life-threatening at perfusate drug concentrations in excess of 20 nmol/ml. In situ lung perfusion for the treatment of unresectable pulmonary tumors may be clinically applicable.
Minchin
R F
RF
Developmental Therapeutics Program, National Cancer Institute, Bethesda, Maryland.
Johnston
M R
MR
Schuller
H M
HM
Aiken
M A
MA
Boyd
M R
MR
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011013:Pneumonectomy; D013997:Time Factors
D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007703:Peptidyl-Dipeptidase A