DIFFERENTIAL EFFECT OF TAXOL IN RAT PRIMARY AND METASTATIC PROSTATE TUMORS - SITE-DEPENDENT PHARMACODYNAMICS

Purpose. This study compared the sensitivity of rat prostate MAT-LyLu primary and lymph node metastatic tumors to taxol. Methods. Tumors wer e established by subcutaneous implantation of tumor cells in a hind le g (primary site) of male Copenhagen rats. Lymph node metastases were u sed for serial transplantation. Eleven pairs of primary and metastatic tumors between the sixth and twentieth generations were harvested and maintained as 3-dimensional histocultures. The effects of taxol (24 h r treatment at 1 nM to 10 mu M) were measured by the appearance of apo ptotic cells, and by the inhibition of DNA precursor (thymidine) incor poration. To determine the basis of differential sensitivity of primar y and metastatic tumors to the DNA inhibition, we examined the express ion of multidrug resistance p-glycoprotein (Pgp) and the accumulation of H-3-taxol after 24 hr exposure and the retention after a 48 hr wash out period. Results. The fraction of apoptotic cells increased linearl y with the logarithm of taxol concentration to a maximal value of 25%; the concentration-response curves for primary and metastatic tumors w ere superimposable. Taxol produced a sigmoidal, concentration-dependen t inhibition of thymidine incorporation; the maximal inhibition of sim ilar to 40% was reached at 0.1 and 1 mu M for primary and metastatic t umors, respectively. Within the primary or metastatic subgroups, the I C30 (drug concentration that produced a 30% inhibition of DNA synthesi s) among consecutive generations varied by < 5 fold, but the primary t umor consistently showed a lower IC30 than the daughter or the parent metastatic tumor (mean, 20-fold; median, 15-fold; range, 5- to 56-fold ). The finding that the lower drug sensitivity in metastatic tumors wa s not exhibited in its daughter primary tumor but was regained in its daughter metastatic tumors suggests that the chemoresistant phenotype is maintained only in lymph nodes and not in the primary site. There w ere no differences in the Pgp status (neither tumor expressed Pgp), ac cumulation and retention of taxol in primary and metastatic tumors. Co nclusions. Taxol induced apoptosis and inhibited DNA synthesis in the rat MAT-LyLu primary and lymph node metastatic tumors. The apoptotic e ffect was not different among the two tumors, whereas the primary tumo r was more sensitive to the inhibition of DNA synthesis. The different ial sensitivity of the two tumors to the DNA effect is not associated with a difference in Pgp expression, drug accumulation nor drug retent ion, and appears to be associated with changes that are linked to lymp h node metastasis.