Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: Clinical implications

Elevated tuner interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors , The etiology of tumor interstitial hypertension is poorly understood. We have postulated that the solid stress generated by tumor cells growing in a confined space compresses blood vessels and increases tumor microvascular pressure and IFP. To test the hypothesis that neoplastic cell loss would de compress blood vessels and lower IFP, we induced apoptosis in tumors with p aclitaxel and docetaxel, Taxanes inhibited the growth of the murine mammary carcinoma (MCa-IV) and of the human soft tissue sarcoma (HSTS-26T), Taxane s induced apoptosis and reduced the density of intact neoplastic cells in b oth MCa-IV and HSTS-26T, To determine whether neoplastic cell loss decompre ssed blood vessels, we measured the diameter of tumor vessels in HSTS-26T t umors implanted in transparent dorsal skin fold chambers, At 48 and 96 h af ter paclitaxel, the diameter of tumor vessels was significantly increased. The increase in vascular diameters was associated with reductions in microv ascular pressure and IFP. The changes in neoplastic cell density and IFP we re also correlated. In the human glioblastoma U87, which is resistant to pa clitaxel, the IFP and cellular density were not modified by paclitaxel trea tment. Collectively, these results support the hypothesis that solid stress generated by neoplastic cell proliferation increases vascular resistance a nd IFP. The increase in vessel diameter induced by paclitaxel and docetaxel suggests that taxanes could improve tumor response by increasing the vascu lar surface area for delivery of therapeutic agents.