BACKGROUND: Previous studies indicate that Cremophor EL (CEL), the excipient for Taxol, a clinical preparation of paclitaxel, has biologic properties per se. METHODS: The cytotoxic activity of Taxol and its solvents CEL/ethanol, paclitaxel in ethanol, and 14 other cytotoxic drugs was investigated in vitro in 10 human carcinoma cell lines and 183 tumor samples from patients with tumors of various types. Cytotoxicity was determined by the fluorometric microculture cytotoxicity assay. RESULTS: In the cell lines, Taxol was generally more active than paclitaxel; this may have been due to an additive effect of the diluent. This activity was pronounced in sublines expressing tubulin-associated and P-glycoprotein-mediated drug resistance, indicating involvement of these mechanisms in paclitaxel resistance and their modulation by CEL. Taxol and paclitaxel were highly cross-resistant to other tubulin-active agents, whereas the low cytotoxic effect of CEL seemed unrelated to other drugs. In the samples from patients, Taxol was less active than in the cell lines but showed a differential activity that corresponded reasonably well with that in the clinic. CEL and Taxol were similarly active, indicating that paclitaxel did not add substantially to the activity of Taxol. CONCLUSIONS: Whereas the cell line data clearly confirmed the well-known properties of paclitaxel, a more valid model using tumor cells from patients demonstrated that CEL significantly contributes to the efficacy of Taxol in vitro. The clinical relevance of this finding remains to be elucidated.
BACKGROUND: Previous studies indicate that Cremophor EL (CEL), the excipient for Taxol, a clinical preparation of paclitaxel, has biologic properties per se. METHODS: The cytotoxic activity of Taxol and its solvents CEL/ethanol, paclitaxel in ethanol, and 14 other cytotoxic drugs was investigated in vitro in 10 humancarcinoma cell lines and 183 tumor samples from patients with tumors of various types. Cytotoxicity was determined by the fluorometric microculture cytotoxicity assay. RESULTS: In the cell lines, Taxol was generally more active than paclitaxel; this may have been due to an additive effect of the diluent. This activity was pronounced in sublines expressing tubulin-associated and P-glycoprotein-mediated drug resistance, indicating involvement of these mechanisms in paclitaxel resistance and their modulation by CEL. Taxol and paclitaxel were highly cross-resistant to other tubulin-active agents, whereas the low cytotoxic effect of CEL seemed unrelated to other drugs. In the samples from patients, Taxol was less active than in the cell lines but showed a differential activity that corresponded reasonably well with that in the clinic. CEL and Taxol were similarly active, indicating that paclitaxel did not add substantially to the activity of Taxol. CONCLUSIONS: Whereas the cell line data clearly confirmed the well-known properties of paclitaxel, a more valid model using tumor cells from patients demonstrated that CEL significantly contributes to the efficacy of Taxol in vitro. The clinical relevance of this finding remains to be elucidated.
Authors: Zachary J Walker; Michael J VanWyngarden; Brett M Stevens; Diana Abbott; Andrew Hammes; Christophe Langouët-Astrie; Clayton A Smith; Brent E Palmer; Peter A Forsberg; Tomer M Mark; Craig T Jordan; Daniel W Sherbenou Journal: Blood Adv Date: 2020-04-28