title: 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: IPSEN Innovation, IPSEN, Paris, France.
authors: Florence
authors: F
authors: Meyer-Losic
authors: Simon P
authors: SP
authors: Newman
authors: Joanna M
authors: JM
authors: Day
authors: Michael J
authors: MJ
authors: Reed
authors: Philip G
authors: PG
authors: Kasprzyk
authors: Atul
authors: A
authors: Purohit
authors: Paul A
authors: PA
authors: Foster
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000556:secondary; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004963:Estrenes / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000556:secondary; D008321:Mammary Glands, Animal; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017239:Paclitaxel / Q000009:adverse effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051381:Rats; D016019:Survival Analysis; D014183:Transplantation, Heterologous
chemical_list: C526438:2-methoxyestradiol-3,17-O,O-bis(sulfamate); D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D004963:Estrenes; D017239:Paclitaxel