Dose-related doxorubicin effect in an orthotopic secondary lung cancer screen

Lung cancer is the leading cause of cancer-related death of both sexes in the United States and promises to be a major problem in the world community for decades. We are developing an orthotopic (organ specific) secondary screening system to measure the uptake and efficacy of new lung cancer agents. The elements of the system are: (1) orthotopic growth of a model human lung cancer (NCI-H460 large cell carcinoma) in the right caudal lobe of the nude rat; (2) 1-hr ex vivo pulmonary perfusion treatment of the tumor-bearing lungs; and (3) soft agar clonogenic assay of the enzymatically disaggregated tumor cells. This study characterizes dose-response aspects of the system. Perfusion of tumor-bearing lungs with 0, 1, 10, and 100 micrograms/ml doxorubicin resulted in a dose-related reduction in surviving fraction from 1.01 +/- 0.41 to 0.019 +/- 0.006 (P < 0.05) without significant treatment-related increases in lung weight or perfusion pressure. Tumor and lung drug levels were also dose-related, with lung levels exceeding tumor levels at all doses. The tumor drug level at the 100 micrograms/ml dose was 62 +/- 16 ng/mg. There was a strong negative correlation between the measured tumor drug level and surviving fraction in the clonogenic assay (R2 = 0.47, P = 0.0005). This new screening system is capable of demonstrating dose-related uptake and tumoricidal activity of doxorubicin on an orthotopic, model human large cell lung carcinoma. It may be useful for the secondary screening of agents active against human lung cancer.