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Changes in VEGF level and tumor growth characteristics during lewis lung carcinoma progression towards cis-DDP resistance.

AIM
To study the relationship between tumor angiogenic potential and its growth and metastasis using Lewis lung carcinoma (LLC) models with different degree of resistance to cis-diamminedichloroplatinum (cis-DDP).


METHODS
LLC and its two cis-DDP-resistant variants (LLC-9 LLC-19), were used. For determination of angiogenic potential of LLC, LLC-9 and LLC-19, the level of VEGF production by these tumor cells in vitro and the level of circulating VEGF during tumor growth in vivo was measured by enzyme-linked immunosorbent assay.


RESULTS
Progressive decrease of LLC-9 and LLC-19 sensitivity to action of cis-DDP evidenced in vitro (IC50=0.0077+/-0.0005 mg/ml and 0.0156+/-0.0008 mg/ml respectively vs. 0.004+/-0.0003 mg/ml for LLC, p<0.05) and in vivo (index of primary tumor growth inhibition by cis-DDP was 26% and 3% respectively vs. 46%; index of metastasis inhibition--46% and 11% vs. 65%, p<0.05) was accompanied by the significant changes of tumor angiogenic potential. The level of VEGF production by primary culture of LLC-9 in vitro was 1.5 fold higher (p<0.05) than that by primary culture of LLC, whereas there were no differences in the level of VEGF production between LLC-19 and LLC. The level of circulating VEGF drastically increased in the initial phase of LLC-9 and LLC-19 growth in vivo, whereas in LLC bearing mice the dynamic changes of VEGF level are characterized by the presence of long-term latent period (t(lag)=17.0+/-0.3 days). In LLC bearing mice the character of changes of circulating VEGF level significantly correlated with the number of metastases (p<0.001) but not with tumor volume; while in LLC-9 bearing mice - with tumor volume (p<0.01) and the number of metastases (p<0.05). Although maximum level of circulating VEGF was significantly (p<0.05) higher in LLC-9 bearing mice than that in LLC bearing mice, maximum number of lung metastases was significantly (p<0.05) lower in LLC-9 bearing mice vs LLC. In contrast to LLC-9, in LLC-19 bearing mice the level of metastatic injury was significantly elevated (p<0.05) and the level of circulating VEGF considerably correlated with both tumor volume (p<0.01) and metastatic index (p<0.01).


CONCLUSION
There is revealed a direct correlation between the level of circulating VEGF and all parameters of tumor progression observed only in the cases of highly resistant tumors, whilst elevation of circulating VEGF level during tumor growth in vivo could be considered as a marker of metastasis not dependent on a drug resistance of tumor.