Abstract
Despite paclitxael's clinical success, treating hormone-refractory breast cancer remains challenging. Paclitaxel has a poor pharmacological profile, characterized by a low therapeutic index (TIX) caused by severe dose limiting toxicities, such as neutropenia and peripheral neuropathy. Consequently, new drugs are urgently required. STX140, a compound previously shown to have excellent efficacy against many tumors, is here compared to paclitaxel in three translational in vivo breast cancer models, a rat model of peripheral neuropathy, and through pharmacological testing. Three different in vivo mouse models of breast cancer were used; the metastatic 4T1 orthotopic model, the C3(1)/SV40 T-Ag model, and the MDA-MB-231 xenograft model. To determine TIX and pharmacological profile of STX140, a comprehensive dosing regime was performed in mice bearing MDA-MD-231 xenografts. Finally, peripheral neuropathy was examined using a rat plantar thermal hyperalgesia model. In the 4T1 metastatic model, STX140 and paclitaxel significantly inhibited primary tumor growth and lung metastases. All C3(1)/SV40 T-Ag mice in the control and paclitaxel treated groups developed palpable mammary cancer. STX140 blocked 47% of tumors developing and significantly inhibited growth of tumors that did develop. STX140 treatment caused a significant (P<0.001) survival advantage for animals in early and late intervention groups. Conversely, in C3(1)/SV40 T-Ag mice, paclitaxel failed to inhibit tumor growth and did not increase survival time. Furthermore, paclitaxel, but not STX140, induced significant peripheral neuropathy and neutropenia. These results show that STX140 has a greater anti-cancer efficacy, TIX, and reduced neurotoxicity compared to paclitaxel in C3(1)/SV40 T-Ag mice and therefore may be of significant benefit to patients with breast cancer.
Highlights
Use of microtubule-targeting agents, such as the taxanes, to treat early- and late-stage breast cancer is common
To prepare for Phase I trials, we investigate the toxicological and neuropathic profile of STX140 compared to paclitaxel in a mouse model of peripheral neuropathy
We further investigated STX140 neurotoxicity profile compared to paclitaxel using a thermal hyperalgesia method of peripheral neuropathy
Summary
Use of microtubule-targeting agents, such as the taxanes, to treat early- and late-stage breast cancer is common. Taxane efficacy is compromised by dose-limiting toxicities such as neutropenia and neurotoxicity. Hypersensitivity reactions are triggered by the presence of non-ionic surfactant, CremophorH EL, required in taxane formulations [1]. These factors result in poor physiological tolerance, and optimal anti-tumor doses can only be administered intermittently. There has been some success in developing new taxane analogs, notably nab-paclitaxel and cabazitaxel, recent strategies aimed at lowering taxane associated toxicities have shown only limited success [2]. There remains an unmet clinical requirement for compounds with both excellent efficacy against breast cancer and a reduced toxicity profile
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