title: Evaluation of a reductively activated duocarmycin prodrug against murine and human solid cancers.
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.
authors.affiliation: Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA. gvielhauer@kumc.edu
authors.forename: George A
authors.initials: GA
authors.lastname: Vielhauer
authors.forename: Megan
authors.initials: M
authors.lastname: Swink
authors.forename: Nikhil K
authors.initials: NK
authors.lastname: Parelkar
authors.forename: James P
authors.initials: JP
authors.lastname: Lajiness
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Wolfe
authors.forename: Dale
authors.initials: D
authors.lastname: Boger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D007211:Indoles; D011355:Prodrugs
keywords: breast; cancer; duocarmycin; lung; orthotopic tumor model; prodrug; prostate