Acute toxicity of irinotecan in the ex-vivo isolated perfused human lung model--high-dose therapy during isolated perfusion without acute toxic lung edema.
In many cases unresectable or recurrent pulmonary metastases do not respond to systemic chemotherapy or the side-effects are not acceptable. Based on the results of our experiments the isolated lung perfusion could improve the option of local chemotherapy. Parameters for lung edema formation (relative increase in weight, gas exchange, histopathology) were evaluated during extracorporal ventilation and reperfusion of lobes resected for lung cancer. Drug concentration was measured in lung tissue, tumour and hilar lymphnodes. Irinotecan was detected in concentrations from 0.06 to 35.3 mg/g in correlation to the content of drug in the perfusate. None of the preparations perfused with a concentration up to 20 times higher than the concentration for systemic application generated a drug-dependent reperfusion edema. A toxic injury of lung parenchyma could be excluded histopathologically. Therefore, we documented that even a perfusion with 2000 mg/l does not cause any relevant acute toxic damages of the lung parenchyma. The transferability of pharmacological data gained through the IHLP is excellent and minimises potential adverse reactions for the patients during phase I trials. As an alternative to systemically applied cytostatic drugs the isolated lung perfusion with irinotecan deserves further attention due to its interesting pharmacological profile with regard to tumor selectivity.
Department of Thoracic Surgery, Lungenklinik Hemer, Centre for Pneumology and Thoracic Surgery, Theo-Funccius-Str. 1, D-58675 Hemer, Germany. cbiancosino@gmx.de
Christian
C
Biancosino
Marcus
M
Albert
Albert
A
Linder
D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000077146:Irinotecan; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D009924:Organ Culture Techniques; D009929:Organ Size / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D011652:Pulmonary Circulation / Q000187:drug effects*; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D010100:Oxygen; D002166:Camptothecin