Aerosol gemcitabine: preclinical safety and in vivo antitumor activity in osteosarcoma-bearing dogs.
BACKGROUND
Osteosarcoma is the most common skeletal malignancy in the dog and in young humans. Although chemotherapy improves survival time, death continues to be attributed to metastases. Aerosol delivery can provide a strategy with which to improve the lung drug delivery while reducing systemic toxicity. The purpose of this study is to assess the safety of a regional aerosol approach to chemotherapy delivery in osteosarcoma-bearing dogs, and second, to evaluate the effect of gemcitabine on Fas expression in the pulmonary metastasis.


METHODS
We examined the systemic and local effects of aerosol gemcitabine on lung and pulmonary metastasis in this relevant large-animal tumor model using serial laboratory and arterial blood gas analysis and histopathology and immunohistochemistry, respectively.


CONCLUSIONS
Six hundred seventy-two 1-h doses of aerosol gemcitabine were delivered. The treatment was well tolerated by these subjects with osteosarcoma (n = 20). Aerosol-treated subjects had metastatic foci that demonstrated extensive, predominately central, intratumoral necrosis. Fas expression was decreased in pulmonary metastases compared to the primary tumor (p = 0.008). After aerosol gemcitabine Fas expression in the metastatic foci was increased compared to lung metastases before treatment (p = 0.0075), and even was higher than the primary tumor (p = 0.025). Increased apoptosis (TUNEL) staining was also detected in aerosol gemcitabine treated metastasis compared to untreated controls (p = 0.028). The results from this pivotal translational study support the concept that aerosol gemcitabine may be useful against pulmonary metastases of osteosarcoma. Additional studies that evaluate the aerosol route of administration of gemcitabine in humans should be safe and are warranted.
Rodriguez
Carlos O
CO
William R. Prichard Veterinary Medical Teaching Hospital, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. dvmrodriguez@ucdavis.edu
Crabbs
Torrie A
TA
Wilson
Dennis W
DW
Cannan
Virginia A
VA
Skorupski
Katherine A
KA
Gordon
Nancy
N
Koshkina
Nadya
N
Kleinerman
Eugenie
E
Anderson
Peter M
PM
D000336:Aerosols; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004285:Dogs; D053222:Fas Ligand Protein / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D012516:Osteosarcoma / Q000188:drug therapy* / Q000556:secondary; D019014:fas Receptor / Q000502:physiology; D000093542:Gemcitabine
D000336:Aerosols; D000964:Antimetabolites, Antineoplastic; D053222:Fas Ligand Protein; D019014:fas Receptor; D003841:Deoxycytidine; D000093542:Gemcitabine