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Growth inhibition of established B16-F10 lung metastases by sequential aerosol delivery of p53 gene and 9-nitrocamptothecin

Gene Therapy volume 9, pages 353–357 (2002)Cite this article

Abstract

Growth inhibition of established tumor metastases in the lungs poses a difficult challenge for most clinical settings in spite of extensive multi-modality approaches. Aerosol delivery of drugs and genes holds promise for the treatment of disseminated lung metastases, since aerosol delivery can target the lungs specifically and uniformly. We previously demonstrated that aerosol delivery of dilauroylphosphatidylcholine liposome formulation of 9-nitrocamptothecin (9NC-DLPC) inhibits B16-F10 melanoma lung metastases. Aerosol delivery of polyethleneimine-p53 DNA (PEI-p53) complexes results in a similar anti-tumor effect in the B16-F10 model. In both these previous studies, the protocols were designed to inhibit development of lung metastases. In this study we demonstrate, using the B16-F10 melanoma lung metastasis model, that sequential aerosol delivery of PEI-p53 and 9NC-DLPC acts additively to inhibit growth of established B16-F10 tumor metastases in the lungs. Mice injected with B16-F10 cells and treated with a combination of 9NC-DLPC (twice weekly) and PEI-p53 (once weekly) aerosol complexes starting on day 11 after tumor inoculation, exhibited a highly significant (P < 0.01) reduction in the number of visible tumor foci as compared with untreated mice or mice treated with either single agent alone, or with a combination of 9NC and a control plasmid. There was a highly significant reduction in the tumor burden, as well as the lung weights for the 9NC and p53 combination group (P < 0.001 as compared with other groups). Moreover, the doses of p53 gene and 9NC in the combination group were reduced at least two-fold as compared with our previous single agent studies, but still achieved significant tumor inhibition. Furthermore, the sequential aerosol delivery of p53 and 9NC lead to a 30–40% increase in the mean survival time of these mice, as compared with animals in different control groups. The data suggest that the combination of 9NC and p53 gene delivered by aerosol is an attractive strategy for growth inhibition of established tumor metastases in the lungs.

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Acknowledgements

The research was funded by the Clayton Foundation for Research, Houston TX. AG and CLD were also supported, in part, by an Advanced Technology Program Grant from the Texas Higher Education Coordinating Board (No. 004949-0129-1999 to C Densmore).

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  1. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA

    A Gautam, J.C Waldrep, C.L Densmore, N Koshkina, S Melton, L Roberts, B Gilbert & V Knight

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  1. A Gautam
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  2. J.C Waldrep
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  4. N Koshkina
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Gautam, A., Waldrep, J., Densmore, C. et al. Growth inhibition of established B16-F10 lung metastases by sequential aerosol delivery of p53 gene and 9-nitrocamptothecin. Gene Ther 9, 353–357 (2002). https://doi.org/10.1038/sj.gt.3301662

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