Abstract
Aim: To characterize gemcitabine aerosol, its in vitro activity against lung cancer cells, its deposition, and tolerance in a non-human primate model. Methods: In vitro cytotoxicity of nebulized gemcitabine against NCI-H460 and A549 lung cancer cells was tested using a growth inhibition assay and compared with non-nebulized gemcitabine. The 99mTc-DTPA-radiolabeled gemcitabine aerosol was characterized by cascade impaction and the gemcitabine mass/99mTc activity relationship was established for further quantitative nuclear imaging. Nine weekly inhalations at a target dose of 1 mg/kg body weight of gemcitabine were performed in three baboons using dynamic scintigraphic acquisitions for continuous monitoring of gemcitabine delivery during inhalation. Gemcitabine plasma concentrations were measured during the first inhalation. Results: Growth inhibition assays for both NCI-H460 and A549 cells did not differ between nebulized and non-nebulized gemcitabine. Aerosol characterization showed a particle mass median aerodynamic diameter of 3.7±0.8 μm and a linear relationship between gemcitabine mass (y) and 99mTc activity (x) (y=0.82x − 10−5, R 2=0.88). No toxicity was observed after nine weekly inhalations of a mean dose of gemcitabine of 11.1 mg (88% of the target dose) as assessed from scintigraphic data. A dose-dependent peak plasma concentration of gemcitabine (20–74 ng/ml) was observed by the tenth minute of inhalation. Conclusions: We have characterized a gemcitabine aerosol suitable for intrathoracic airway deposition and demonstrated that jet nebulization does not alter the cytotoxic properties of the drug. In a primate model, we have developed a scintigraphic procedure for the monitoring of aerosol deposition, and we have demonstrated the safety of nine weekly aerosol administrations of gemcitabine.
Similar content being viewed by others
References
Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47:936–942
Dequin PF, Delatour F, Faurisson F, Valat C, Lemarié E, Le Pape A, Diot P (1997) Characterization on the bench of an amikacin aerosol before clinical studies. J Aerosol Med 10:221–230
Diot P, Bonfils P, Faurisson F, Fauroux B, Dautzenberg B (2000) Proposed guidelines for aerosol therapy by means of nebulizers. Eur Respir Rev 10:206–209
Diot P, Dequin PF, Rivoire B, Gagnadoux F, Faurisson F, Diot E, Boissinot E, Le Pape A, Palmer L, Lemarié E (2001) Aerosol and anti-infectious agents. J Aerosol Med 14:55–64
Edelman M, Quam H, Mullins B (2001) Interactions of gemcitabine, carboplatin and paclitaxel in molecularly defined non-small-cell lung cancer cell lines. Cancer Chemother Pharmacol 48:141–144
Gagnadoux F, Le Pape A, Lemarié E, Lerondel S, Valo I, Leblond B, Racineux JL, Urban T (2005) Aerosol delivery of chemotherapy in an orthotopic model of lung cancer. Eur Respir J (in press)
Gagnadoux F, Le Pape A, Urban T, Montharu J, Vecellio L, Dubus JC, Leblond V, Diot P, Grimbert D, Racineux JL, Lemarié E (2005) Safety of pulmonary administration of gemcitabine in rats. J Aerosol Med 18:198–206
Hershey AE, Kurman ID, Forrest LJ, Bohling CA, Stonerook M, Placke ME, Imondi AR, Vail DM (1999) Inhalation chemotherapy for macroscopic primary or metastatic lung tumors: proof of principle using dogs with spontaneously occurring tumors as a model. Clin Cancer Res 5:2653–2659
Hollinger MA (1995) Tables. In: MJ Derelanko, Hollinger MA (eds) Handbook of toxicology. CRC Press, New York
Kaway M, Esumi Y, Ishizaki S, Gunji S, Seki H (1995) Metabolism of gemcitabine in rat and dogs. Xenobiotica 25:405–416
Koshkina NV, Kleinerman ES (2005) Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases. Int J Cancer 116:458–463
Lerondel S, Le Pape A, Sené C, Faure L, Bernard S, Diot P, Nicolis E, Mehtali M, Lusky M, Cabrini G, Pavirani A (2001) Radioisotopic imaging allows optimization of adenovirus lung deposition for cystic fibrosis gene therapy. Hum Gene Ther 12:1–11
Lipworth BJ (1996) Pharmacokinetics of inhaled drugs. Br J Clin Pharmacol 42:697–706
Mackey JR, Mani RS, Selner M, Mowles D Young JD, Belt JA, Crawford CR, Cass CE (1998) Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 58:4349–4357
Morrow PE (1974) Aerosol characterization and deposition. Am Rev Respir Dis 110:88–89
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Perng RP, Cheng YM, Ming-Lui J, Tsai CM, Lin WC, Yang KY, Whang-Peng J (1997) Gemcitabine versus the combination of cisplatin and etoposide in patients with inoperable non-small-cell lung cancer in a phase II randomized study. J Clin Oncol 15:2097–2102
Sharma S, White D, Imondy AR, Placke ME, Vail DM, Kris MG (2001) Development of inhalational agents for oncologic use. J Clin Oncol 19:1839–1847
Tatsumura T, Koyama S, Tsujimoto M, Kitagawa M, Kagamimori S (1993) Further study of nebulisation chemotherapy, a new chemotherapeutic method in the treatment of lung carcinomas: fundamental and clinical. Br J Cancer 68:1146–1149
Tolis C, Peters GJ, Ferreira GC, Pinedo HM, Giaccone G (1999) Cell cycle disturbances and apoptosis induced by topotecan and gemcitabine on human lung cancer cell lines. Eur J Cancer 35:796–807
Vecellio L, Chantrel G, Grimbert D, De Monte M, Diot P (2003) Influence of drug physico chemical characteristics on the performances of a new single use jet nebulizer. The Aerosol Society, DDL 14 (Drug Deliv Lungs XIV)
Verschraegen CF, gilbert BE, Loyer E, Huaringa A, Walsh G, Newman RA, Knight V (2004) Clinical evaluation of the delivery and safety of aerosolized liposomal 9-nitro-20(s)-camptothecin in patients with advanced pulmonary malignancies. Clin Cancer Res 10:2319–2326
Wang Z, Chen HT, Roa W, Finlay WH (2003) Farnesol for aerosol inhalation: nebulization and activity against human lung cancer cells. J Pharm Pharmaceut Sci 6:95–100
Yeates D, Hameister WM (1992) Alveolar epithelial permeability in baboons: histamine and capsaicin. J Physiol 450:363–74
Acknowledgements
Emmanuelle BOLL-BATAILLE is acknowledged for her participation in growth inhibition assays.
Author information
Authors and Affiliations
Corresponding author
Additional information
Research supports: This study was supported by a grant from the Comité Départemental du Maine-et-Loire de la Ligue Nationale Contre le Cancer.
Rights and permissions
About this article
Cite this article
Gagnadoux, F., Leblond, V., Vecellio, L. et al. Gemcitabine aerosol: in vitro antitumor activity and deposition imaging for preclinical safety assessment in baboons. Cancer Chemother Pharmacol 58, 237–244 (2006). https://doi.org/10.1007/s00280-005-0146-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-005-0146-9