Fatal pulmonary toxicity can be consistently produced in
L1210 leukemia-bearing mice by single therapeutic doses of
cyclophosphamide,
BCNU, and
mitomycin C but not by
adriamycin. Lung toxicity is principally determined by an existing
tumor burden at the time of
drug administration. Thus when any of the four chemotherapeutic agents was given 5 days after L1210
transplantation there was no mortality. Pulmonary pathology in these mice was equivalent to that noted in normal mice receiving identical
drug treatment or to that noted in untreated L1210-bearing mice sacrificed 7, 8, or 10 days after
tumor transplantation. When
chemotherapy was delayed to day 7 after L1210
transplantation for
mitomycin C or to day 8 after
transplantation for
BCNU and
cyclophosphamide, more severe pulmonary toxicity was found. Mortality within the first 5 days of treatment was 38, 50, and 80%, respectively. Pulmonary pathology included moderate to severe vascular congestion and
interstitial pneumonitis, diffuse pulmonary
hemorrhage often involving the entire pulmonary parenchyma,
pulmonary edema, and alveolar cell
metaplasia. A unique finding, associated with
cyclophosphamide treatment, was the occurrence of perivascular-intramural
edema of the walls of medium-size pulmonary vessels. It is hypothesized that stasis within the pulmonary capillary circulation, resulting from advanced
tumor growth and from
drug treatment, may contribute to the development of
chemotherapy-related toxicity.