Preclinical optimization of a broad-spectrum anti-bladder cancer tri-drug regimen via the Feedback System Control (FSC) platform.

Abstract

Therapeutic outcomes of combination chemotherapy have not significantly advanced during the past decades. This has been attributed to the formidable challenges of optimizing drug combinations. Testing a matrix of all possible combinations of doses and agents in a single cell line is unfeasible due to the virtually infinite number of possibilities. We utilized the Feedback System Control (FSC) platform, a phenotype oriented approach to test 100 options among 15,625 possible combinations in four rounds of assaying to identify an optimal tri-drug combination in eight distinct chemoresistant bladder cancer cell lines. This combination killed between 82.86% and 99.52% of BCa cells, but only 47.47% of the immortalized benign bladder epithelial cells. Preclinical in vivo verification revealed its markedly enhanced anti-tumor efficacy as compared to its bi- or mono-drug components in cell line-derived tumor xenografts. The collective response of these pathways to component drugs was both cell type- and drug type specific. However, the entire spectrum of pathways triggered by the tri-drug regimen was similar in all four cancer cell lines, explaining its broad spectrum killing of BCa lines, which did not occur with its component drugs. Our findings here suggest that the FSC platform holds promise for optimization of anti-cancer combination chemotherapy.

• Authors: Qi Liu, Cheng Zhang, Xianting Ding, Hui Deng, Daming Zhang, Wei Cui, Hongwei Xu, Yingwei Wang, Wanhai Xu, Lei Lv, Hongyu Zhang, Yinghua He, Qiong Wu, Moshe Szyf, Chih-Ming Ho, Jingde Zhu
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 11464 (Jun 19 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26088171 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease Models, Animal
• Drug Evaluation, Preclinical (methods)
• Drug Resistance, Neoplasm
• Drug Therapy, Combination
• Humans
• Mice
• Models, Theoretical
• Signal Transduction (drug effects)
• Tumor Burden (drug effects)
• Urinary Bladder Neoplasms (drug therapy, metabolism, pathology)
• Xenograft Model Antitumor Assays