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Evaluation of a reductively activated duocarmycin prodrug against murine and human solid cancers
George A Vielhauer1, Megan Swink, Nikhil K Parelkar
1Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA. gvielhauer@kumc.edu
Abstract:
In treating cancer with clinically approved chemotherapies, the high systemic toxicity and lack of selectivity for malignant cells often result in an overall poor response rate. One pharmacological approach to improve patient response is to design targeted therapies that exploit the cancer milieu by reductively activating prodrugs, which results in the selective release of the free drug in the tumor tissue. Previously, we characterized prodrugs of seco-CBI-indole 2 (CBI-indole 2) designed to be activated in hypoxic tumor microenvironments, wherein the tumor maintains higher concentrations of "reducing" nucleophiles capable of preferentially releasing the free drug by nucleophilic attack on a weak N-O bond. Of these prodrugs, BocNHO-CBI-indole 2 (BocNHO) surpassed the efficacy of the free drug, CBI-indole 2, when examined in vivo in the murine L1210 leukemia model and demonstrated reduced toxicity suggesting a targeted or sustained release in vivo. Herein, we further examine the biological activity of the BocNHO prodrug in murine breast cancer, as well as human prostate and lung cancer cell lines, in vitro. Notably, BocNHO manifests potent antiproliferative and cytotoxic activity in all three tumor cell lines. However, in comparison to the activity observed in the murine cancer cell line, the human cancer cell lines were less sensitive, especially at early timepoints for cytotoxicity. Based on these findings, BocNHO was tested in a more clinically relevant orthotopic lung tumor model, revealing significant efficacy and reduced toxicity compared with the free drug. The data suggests that this pharmacological approach to designing targeted therapies is amenable to human solid tumors.
Insights
This study shows BocNHO-CBI-indole 2 (BocNHO) is a targeted cancer therapy prodrug. BocNHO demonstrates efficacy and reduced toxicity in preclinical models, suggesting potential for human solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Clinically approved chemotherapies exhibit high systemic toxicity and poor selectivity, leading to suboptimal cancer treatment outcomes.
- Targeted therapies activating prodrugs in the tumor microenvironment offer a strategy to enhance drug selectivity and efficacy.
- Hypoxia-inducible prodrugs, like those based on seco-CBI-indole 2 (CBI-indole 2), are designed for reductive activation by tumor-specific nucleophiles.
Purpose of the Study:
- To evaluate the in vitro and in vivo efficacy and toxicity of the prodrug BocNHO-CBI-indole 2 (BocNHO).
- To assess BocNHO's activity against murine breast cancer, human prostate cancer, and human lung cancer cell lines.
- To determine BocNHO's therapeutic potential in a clinically relevant orthotopic lung tumor model.
Main Methods:
- In vitro antiproliferative and cytotoxic assays were performed on murine and human cancer cell lines.
- In vivo studies utilized a murine orthotopic lung tumor model.
- Comparative analysis of BocNHO and the free drug CBI-indole 2 regarding efficacy and toxicity.
Main Results:
- BocNHO exhibited potent antiproliferative and cytotoxic activity in all tested cancer cell lines.
- Human cancer cell lines showed reduced sensitivity to BocNHO compared to murine cell lines, particularly at early timepoints.
- In the orthotopic lung tumor model, BocNHO demonstrated significant efficacy with reduced toxicity versus the free drug.
Conclusions:
- The prodrug BocNHO shows promise as a targeted therapy for solid tumors.
- Reductive activation of prodrugs in the tumor microenvironment is a viable strategy for improving cancer treatment.
- Further investigation into BocNHO's potential for clinical application in human cancers is warranted.
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