This is a project to develop new agents for administration in the pre invasive stage of lung cancer. Vitamin A analogues have the greatest reported activity of any of the agent used in chemoprevention of tobacco-related malignancies. The relationship between the administered dose and the resulting in vivo dose at the site of the target organ is poorly understood. We propose to change the route of administration of the retinoid to improve the therapeutic index. This work has been supported by preclinical toxicology studies conducted under a NIH CRADA with Battelle Labs. The amount of drug required to saturate the bronchial epithelium when delivered as an aerosol is significantly lower than the systemic dose required to deliver a comparable amount of drug to the target organ. Early lung cancer exists only in the tracheobronchial tree where the effects of chronic cigarette smoke have caused diffuse cancerous injury. The beneficial effect of retinoids on cancer cell growth is a direct drug/cancer cell interaction. If the airway is effective as a conduit for the carcinogen, it may also be the most effective way of directing retinoids to the affected early lung cancer cells. Aerosolizing retinoids into the airway instead of giving them orally can result in better bioactivity of the chemoprevention agent while potentially causing less frequent systemic side effects since the blood levels after an aerosolized dose will be much lower. We are proceeding to conduct an initial Phase I/II trial of aerosolized retinoids at the Clinical Center. Two papers outlining the success of this effort in tobacco-carcinogen induced lung cancer models in rodents have been published. Due to the substantial progress on this effort, we will be able to start a clinical trial in late 2000. A range of other active cytotoxic agents will also be evaluated to determine if limited intrapulmonary drug exposure is sufficient to control early, small volume lung cancer. A Phase I trial with aerosolized doxirubicin is ongoing which represents a first step in this regard. With recent developments with spiral CT, routine detection of such small primary lesions is expected and this may drive the need for effective aerosolized chemotherapeutic drugs. The preclinical rationale for this approach has been bolstered by a large in vivo experiment with carcinogen-induced lung tumors. In a series of exposures through a range of retinoid doses, a clear dose response emerges as to the success of retinoid to suppress the frequency of lung tumors developing.

National Institute of Health (NIH)
Division of Clinical Sciences - NCI (NCI)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Clinical Sciences
United States
Zip Code
Mulshine, James L; Atkinson, Jane C; Greer, Robert O et al. (2004) Randomized, double-blind, placebo-controlled phase IIb trial of the cyclooxygenase inhibitor ketorolac as an oral rinse in oropharyngeal leukoplakia. Clin Cancer Res 10:1565-73
Ballaz, Santiago; Mulshine, James L (2003) The potential contributions of chronic inflammation to lung carcinogenesis. Clin Lung Cancer 5:46-62
Garayoa, Mercedes; Man, Yan-Gao; Martinez, Alfredo et al. (2003) Downregulation of hnRNP A2/B1 expression in tumor cells under prolonged hypoxia. Am J Respir Cell Mol Biol 28:80-5
Martinez, Alfredo; Lehman, Teresa A; Modali, Rama et al. (2003) Screening of mutations in the ras family of oncogenes by polymerase chain reaction-based ligase chain reaction. Methods Mol Med 74:187-200
Mulshine, James L (2003) Screening for lung cancer: in pursuit of pre-metastatic disease. Nat Rev Cancer 3:65-73
Warner, Elizabeth E; Mulshine, James L (2003) Surgical considerations with lung cancer screening. J Surg Oncol 84:1-6
Mulshine, James L; Hirsch, Fred R (2003) Lung cancer chemoprevention: moving from concept to a reality. Lung Cancer 41 Suppl 1:S163-74