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Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor.

ABSTRACT: We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38-a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a cancer targeting unit (biotin). Upon light activation in cancer cells, PT-1 interferes with DNA re-ligation, diminishes the expression of topoisomerase I, and enhances the expression of inter alia mitochondrial apoptotic genes, death receptors, and caspase enzymes, inducing DNA damage and eventually leading to apoptosis. In vitro and in vivo studies showed significant inhibition of cancer growth and the hybrid system PT-1 thus shows promise as a programmed photo-therapeutic ("phototheranostic").

SUBMITTER: Shin WS

PROVIDER: S-EPMC4931442 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor.

Shin Weon Sup WS Han Jiyou J Kumar Rajesh R Lee Gyung Gyu GG Sessler Jonathan L JL Kim Jong-Hoon JH Kim Jong Seung JS

Scientific reports 20160704

We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38-a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a can ...[more]

PMID: 27374023

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Project description:BACKGROUND:To achieve optimal outcomes, an individual approach is needed in the treatment and care of patients. The potential value of tumor mutational burden (TMB) status and/or programmed cell death ligand 1 (PD-L1) expression as biomarkers to predict which patients are most likely to respond to checkpoint inhibitors has been explored in many studies. The goal of this targeted literature review is to identify data available for TMB status and/or PD-L1 expression that predict response to checkpoint inhibitors and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies. METHODS:Targeted literature searches were performed using electronic medical databases (MEDLINE, Embase, and BIOSIS) and internet searches of specified sites. Bibliographies of key systematic literature reviews and meta-analyses also were reviewed for studies of interest. RESULTS:The review identified 27 studies of non-small cell lung cancer (NSCLC), 40 studies of melanoma, 10 studies of urothelial cancer, and 5 studies of renal cell cancer indications. Studies also were identified in other cancer types, e.g., colorectal, breast, gastric, and Merkel cell cancer and squamous-cell carcinoma of the head and neck. Twelve trials, including six in NSCLC and four in melanoma, evaluated TMB as a predictor of outcomes. A TMB of ?10 mutations per megabase was shown to be an effective biomarker in the CheckMate 227 study. PD-L1 expression was included in the majority of identified studies and was found to predict response in in melanoma and in all types of NSCLC. Prediction of response was not a prespecified analysis in some studies; others had small sample sizes and wide confidence intervals. A clear predictive trend for PD-L1 expression was not identified in renal, breast, gastric, or Merkel cell cancer. CONCLUSION:Based on data contained in this review, assessment of TMB status and PD-L1 expression may help enhance the prediction of response to checkpoint inhibition in some tumors, such as NSCLC and melanoma. In this rapidly growing area of research, further exploratory biomarkers are being investigated including tumor-infiltrating lymphocytes, immune profiling (e.g., effector T cells or regulatory T cells), epigenetic signatures, T-cell receptor repertoire, proteomics, microbiome, and metabolomics.

Dataset Information

Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor.

Publications

Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor.

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