STX140, but not paclitaxel, inhibits mammary tumour initiation and progression in C3(1)/SV40 T/t-antigen transgenic mice.

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.

• Authors: Florence Meyer-Losic, Simon P Newman, Joanna M Day, Michael J Reed, Philip G Kasprzyk, Atul Purohit, Paul A Foster
• Journal: PloS one (PLoS One) Vol. 8 Issue 12 Pg. e80305 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24324595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-methoxyestradiol-3,17-O,O-bis(sulfamate)
• Antigens, Polyomavirus Transforming
• Antineoplastic Agents
• Estrenes
• Paclitaxel

Topics

• Adenocarcinoma (drug therapy, immunology, mortality, secondary)
• Animals
• Antigens, Polyomavirus Transforming (genetics, immunology)
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (immunology, pathology)
• Disease Progression
• Drug Administration Schedule
• Drug Dosage Calculations
• Estrenes (pharmacology)
• Female
• Humans
• Hyperalgesia (drug therapy, immunology, pathology)
• Lung Neoplasms (drug therapy, immunology, mortality, secondary)
• Mammary Glands, Animal
• Mammary Neoplasms, Experimental (drug therapy, immunology, mortality, pathology)
• Mice
• Mice, Transgenic
• Paclitaxel (adverse effects)
• Peripheral Nervous System Diseases (chemically induced, drug therapy, immunology, pathology)
• Rats
• Survival Analysis
• Transplantation, Heterologous