Paclitaxel is one of the most effective and widely used agents in treating a variety of cancers, including endometrial cancer. Because of its poor solubility in water, the current intravenous pharmaceutical paclitaxel is formulated in Cremophor EL and dehydrated in ethanol in equal volumes. Cremophor EL is capable of causing complement activation, which can trigger an immediate hypersensitivity reaction. SPR064 is a pro-drug of paclitaxel which has a much higher solubility as compared to the parent drug; hence, SPR064 can be conveniently formulated in non-cremapor based medium, reducing the risk of cremaphor-related hypersensitivity reactions. The pharmacokinetics and solubility of SPR064 were evaluated in rats. The anti-tumorigenic potential of SPR064 was compared to paclitaxel in endometrial cancer cell lines and a genetically engineered mouse model (Lkbfl/flp53fl/fl ) of endometrial cancer. Overall, SPR064 exhibited improved solubility and better exposure to drug in rats when compared to paclitaxel. SPR064 and paclitaxel inhibited cell proliferation, induced apoptosis, enhanced cellular stress and caused cell cycle G1 arrest in endometrial cancer cell lines, with similar potency. Both SPR064 and paclitaxel reduced tumor weight in the Lkbfl/flp53fl/fl mouse model under obese and lean conditions compared to their respective controls. Immunohistochemical staining demonstrated that SPR064 and paclitaxel significantly reduced the expression of Ki-67 and BCL-xL in the endometrial tumors of both obese and lean mice. In summary, SPR064 has anti-tumorigenic effects that are equivalent to paclitaxel in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Thus, SPR064 may be a promising therapy for endometrial cancer without the significant risk of hypersensitivity reactions seen with paclitaxel.
Keywords: Paclitaxel; SPR064; apoptosis; cell proliferation; endometrial cancer.
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