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A comparison of two orally bioavailable anti-cancer agents, IRC-110160 and STX140
Paul A Foster1, C Stengel, Tauhid Ali
1Endocrinology and Metabolic Medicine and Sterix Ltd., Faculty of Medicine, Imperial College London, St. Mary's Hospital, London W2 1NY, UK.
Unlabelled:
This study characterises two recently developed anticancer agents in vitro and in vivo, 2-methoxyoestra-1,3,5(10), 16-tetraene-3-carboxamide (IRC-110160) and STX140.
Materials And Methods:
Hormone-dependent (MCF-7), hormone-independent (MDA-MB-231) and P-glycoprotein overexpressing (MCF-7Dox) cells were used for proliferation experiments. For the tumour efficacy studies, female nude mice were inoculated with MDA-MB-231 cells.
Results:
IRC-110160 is a potent inhibitor of both MCF-7 and MDA-MB-231 cell proliferation. Furthermore, the potency of IRC-110160 was unaffected by the over-expression of the P-glycoprotein drug efflux pump. IRC-110160 and 2-methoxyoestradiol-3,17-O,O-bis-sulfamate (STX140) induced apoptosis in a similar timeframe in the MDA-MB-231 cell line, but only STX140 caused G2/M arrest in these cells. In the MDA-MB-231 xenograft model 300 mg/kg p.o. (daily) of IRC-110160 and 20 mg/kg p.o. STX140 (daily) both completely inhibited tumour growth; however some toxicity was observed with IRC-110160. After 28 days of daily dosing STX140 (20 mg/kg p.o.) had minimal effect on the white blood population of mice with tumours. The masking of STX140 from white blood cells may be due to its interaction with carbonic anhydrase II (CAII) in the red blood cells. In contrast to STX140, IRC-110160 does not inhibit CAII. These studies highlight the activity of two orally bioavailable anti-cancer agents one of which, STX140, may offer a significant clinical advantage over existing drugs as a common dose limiting factor, haemotoxicity, may be minimised.
Insights
Two novel anticancer agents, IRC-110160 and STX140, show potent in vitro and in vivo efficacy. STX140 demonstrates potential for reduced toxicity, offering a clinical advantage in cancer treatment.
Area of Science:
- Pharmacology
- Oncology
- Drug Discovery
Background:
- Development of novel anticancer agents is crucial for improving cancer therapy.
- Existing treatments often face challenges with drug resistance and toxicity.
- Orally bioavailable agents offer convenience and potential for improved patient compliance.
Purpose of the Study:
- To characterize the in vitro and in vivo anticancer activity of two new agents: 2-methoxyoestra-1,3,5(10), 16-tetraene-3-carboxamide (IRC-110160) and STX140.
- To compare the efficacy and toxicity profiles of IRC-110160 and STX140.
- To investigate the potential mechanisms of action and clinical advantages of these agents.
Main Methods:
- In vitro proliferation assays using hormone-dependent (MCF-7), hormone-independent (MDA-MB-231), and P-glycoprotein overexpressing (MCF-7Dox) cancer cell lines.
- In vivo tumor efficacy studies in a MDA-MB-231 xenograft mouse model.
- Assessment of apoptosis, cell cycle arrest, tumor growth inhibition, and toxicity, including effects on white blood cell populations and carbonic anhydrase II (CAII) interaction.
Main Results:
- IRC-110160 effectively inhibited proliferation in MCF-7 and MDA-MB-231 cells, irrespective of P-glycoprotein expression.
- Both IRC-110160 and STX140 induced apoptosis in MDA-MB-231 cells; STX140 also caused G2/M arrest.
- In vivo, both agents completely inhibited tumor growth in the xenograft model, with IRC-110160 showing some toxicity and STX140 exhibiting minimal impact on white blood cells, potentially due to CAII interaction.
Conclusions:
- IRC-110160 and STX140 are potent, orally bioavailable anticancer agents with demonstrated in vitro and in vivo activity.
- STX140 shows a favorable toxicity profile compared to IRC-110160, with minimal impact on white blood cells, suggesting a potential clinical advantage.
- STX140's interaction with carbonic anhydrase II (CAII) may contribute to its reduced hemotoxicity, warranting further investigation for cancer treatment optimization.
