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Induced prodrug activation by conditional protein degradation.

ABSTRACT: Enzyme prodrug therapies hold potential as a targeted treatment option for cancer patients. However, off-target effects can be detrimental to patient health and represent a safety concern. This concern can be alleviated by including a failsafe mechanism that can abort the therapy in healthy cells. This feature can be included in enzyme prodrug therapies by use of conditional degradation tags, which degrade the protein unless stabilized. We call this process Degradation-Directed Enzyme Prodrug Therapy (DDEPT). Herein, we use traceless shielding (TShld), a mechanism that degrades a protein of interest unless it is rescued by the addition of rapamycin, to test this concept. We demonstrated that TShld rapidly yielded only native protein products within 1h after rapamycin addition. The rapid protection phenotype of TShld was further adapted to rescue yeast cytosine deaminase, a prodrug converting enzyme. As expected, cell viability was adversely affected only in the presence of both 5-fluorocytosine (5-FC) and rapamycin. We believe that the DDEPT system can be easily combined with other targeting strategies to further increase the safety of prodrug therapies.

SUBMITTER: Gaynor AS

PROVIDER: S-EPMC6595225 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Induced prodrug activation by conditional protein degradation.

Gaynor Andrew S AS Chen Wilfred W

Journal of biotechnology 20170911

Enzyme prodrug therapies hold potential as a targeted treatment option for cancer patients. However, off-target effects can be detrimental to patient health and represent a safety concern. This concern can be alleviated by including a failsafe mechanism that can abort the therapy in healthy cells. This feature can be included in enzyme prodrug therapies by use of conditional degradation tags, which degrade the protein unless stabilized. We call this process Degradation-Directed Enzyme Prodrug Th ...[more]

PMID: 28912080

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Project description:Presently, we investigate the mechanisms whereby intratumoral expression of a cyclophosphamide-activating hepatic cytochrome P450 gene enhances therapeutic activity when cyclophosphamide is given on an every 6-day (metronomic) schedule. In P450-deficient 9L gliosarcomas grown in severe combined immunodeficient mice, metronomic cyclophosphamide substantially decreased tumor microvessel density and induced a approximately 70% loss of endothelial cells that began after the second cyclophosphamide treatment. These responses were accompanied by increased expression of the endogenous angiogenesis inhibitor thrombospondin-1 in tumor-associated host cells but by decreased expression in 9L tumor cells. These antiangiogenic responses preceded tumor regression and are likely key to the therapeutic activity of metronomic cyclophosphamide. Unexpectedly, 9L/2B11 tumors, grown from 9L cells infected with retrovirus encoding the cyclophosphamide-activating P450 2B11, exhibited antiangiogenic responses very similar to 9L tumors. This indicates that the tumor endothelial cell population is well exposed to liver-activated cyclophosphamide metabolites and that intratumoral P450 confers limited additional anti-endothelial cell bystander activity. In contrast, an increase in apoptosis, which preceded the antiangiogenic response, was substantially enhanced by intratumoral P450 2B11 expression. 9L/2B11 tumor regression was accompanied by an overall loss of tumor cellularity and by substantial enlargement of remaining P450-immunoreactive tumor cells as the number of P450-positive tumor cell decreased and the P450 protein content declined with cyclophosphamide treatment. We conclude that metronomic cyclophosphamide regresses P450-expressing tumors by two independent but complementary mechanisms: increased tumor cell killing via intratumoral P450-catalyzed prodrug activation, coupled with strong antiangiogenic activity, which is primarily associated with hepatic prodrug activation.

Dataset Information

Induced prodrug activation by conditional protein degradation.

Publications

Induced prodrug activation by conditional protein degradation.

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