Estabelecimento e validação do modelo de tumor de pulmão em rato com o carcinossarcoma de Walker: avaliação do efeito antitumoral da Taliddomida

Abstract

Introduction: Though lung cancer is the most deadly malignancy in man today, therapeutic improvements have been long in coming, partly because of the lack of experimental lung cancer models for the study of the biological behavior and antitumoral effect of new drugs with cytotoxic, immunomodulatory and antiangiogenic action. Objective: To develop a rat lung tumor model with Walker's carcinosarcoma, use computerized tomography imaging for the monitoring of tumor growth, and evaluate the antitumoral action of thalidomide. Methods: Ninety-five female Wistar rats, with an average weight of 210±53g, were randomly assigned to two experimental phases: phase 1 (n=ll) aimed at developing a surgical tumor implantation technique. The animals were anaesthetized intraperitoneally with 40 mg/kg of pentobarbital, then tracheostomized, intubated and submitted to a left-sided thoracotomy for direct injection of the tumoral vehicle into the lung parenchyma. Phase 2 (n=84) consisted of three steps: step 1 (n=13) established the number of cells required for a high tumor take rate (2xl05 cells of Walker's tumor). Step 2 (n=24) established the tumor growth rate (group I, n=8) and the survival rate (group H, n=16). The animals in group I were submitted to thoracic CT scan and necropsy on the 6 day of implantation in order to verify tumor size and histology. Tumor volumes in cm (Dxd /2) obtained with the two methods (necropsy and CT scan) were compared. The animals in group H were weighed daily and followed until death. Step 3 (n=47) evaluated the antitumoral effect of thalidomide (TLD) in the established model. The animals in this step were assigned to four groups: I(n=7), control; H (n=17), 45 mg/kg/d/sc of TLD; m (n=9), 180 mg/kg/d/sc of TLD; and IV (n=14), 45 mg/kg/d/sc of TLD. The rats in groups I, II and HI were submitted to CT scan and necropsy on the 6 day for evaluation of tumor size; in group IV the weight curves and survival rates of the animals were analyzed. Results: The average tumor take rate was 92.8% (64/69), that is, 81.8% in step 1, 100% in step 2, and 92.1% in step 3. Surgical mortality was 14.3% (12/84); three animals were excluded from the study. The tumor sizes obtained through CT scan and through necropsy were similar (r=0.946; p<0.0001). The average survival rate of the rats in step 2 was 10 days. In step 3, TLD-45 and TLD-180 significantly reduced tumor volumes by 76.6% and 77.5%, respectively, as compared to the controls (p<0.05). No significant difference in tumor reduction was observed between TLD-45 and TLD-180. Cachexia was inhibited and survival increased among the animals treated with TLD-45 (12d, Log Rank test: p=0.015) as compared to controls (lOd). Conclusion: The high tumor take rate and positive correlation between data from CT scans and necropsy makes it possible to monitor tumoral growth by CT imaging and thus evaluate the action of antitumoral drugs in vivo without sacrificing the animals. The inhibition of cachexia and tumoral growth in the animals treated with TLD suggests an anticachectic and antitumoral effect in this drug, probably through local and systemic antiinflammatory and immunomodulatory action by blocking the expression of tumor growth factors or inhibiting the synthesis of proinflammatory cytokines, or possibly through some other as yet unidentified mechanism