Prodrugs for Targeted Tumor Therapies: Recent Developments in ADEPT, GDEPT and PMT

Tietze, Lutz F.; Schmuck, Kianga

doi:10.2174/138161211798194459

Cited by 92 publications

(60 citation statements)

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“…This class of prodrugs has also been investigated in gene-directed enzyme prodrug therapy (GDEPT), a strategy that largely depends on the cancer cell-specific delivery and expression of a therapeutic gene (6). Although as a general concept, GDEPT promises to improve the therapeutic index by a dose enhancement effect at the tumor site (7), this technology has yet to progress into the clinic. More attractive targets for anticancer treatment are endogenous tumorspecific holoenzymes.…”

Section: Introductionmentioning

confidence: 99%

Colon Cancer–Specific Cytochrome P450 2W1 Converts Duocarmycin Analogues into Potent Tumor Cytotoxins

Travica

Pors

Loadman

et al. 2013

Clinical Cancer Research

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Purpose: Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents.Experimental Design: The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts.Results: Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue.Conclusion: Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1.

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Section: Introductionmentioning

confidence: 99%

Colon Cancer–Specific Cytochrome P450 2W1 Converts Duocarmycin Analogues into Potent Tumor Cytotoxins

Travica

Pors

Loadman

et al. 2013

Clinical Cancer Research

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“…Duocarmycins are potent cytotoxic agents with IC 50 values in the pmol/L range against different cell lines (22). Despite this high potency, duocarmycins themselves are not applicable for cancer chemotherapy because they cause pronounced myelotoxicity, preventing escalation to therapeutically active regimen.…”

Section: Introductionmentioning

confidence: 99%

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

et al. 2014

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It is generally thought that the anticancer efficacy of antibody-drug conjugates (ADC) relies on their internalization by cancer cells. However, recent work on an ADC that targets fibronectin in the tumor microenvironment suggests this may not be necessary. The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization. Cancer Res; 74(9); 2569-78. Ó2014 AACR.

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“…The enzyme may be directed to cancer cells as a conjugate with an antibody (antibody-directed enzyme/prodrug therapy, ADEPT), as polymer-based nanoparticles (PDEPT), genetically using engineered non-replicative viruses (GDEPT) or even whole cells (42,43). In particular, the hypoxic tumor microenvironment, which hinders passive drug distribution, can be targeted using engineered bacterial spores of the anaerobic Clostridium sp.…”

Section: Active Conversion Of Cancer-targeted Prodrugsmentioning

confidence: 99%

Prodrug Applications for Targeted Cancer Therapy

Giang

Boland

Poon

2014

AAPS J

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Abstract. Prodrugs are widely used in the targeted delivery of cytotoxic compounds to cancer cells. To date, targeted prodrugs for cancer therapy have achieved great diversity in terms of target selection, activation chemistry, as well as size and physicochemical nature of the prodrug. Macromolecular prodrugs such as antibody-drug conjugates, targeted polymer-drug conjugates and other conjugates that self-assemble to form liposomal and micellar nanoparticles currently represent a major trend in prodrug development for cancer therapy. In this review, we explore a unified view of cancer-targeted prodrugs and highlight several examples from recombinant technology that exemplify the prodrug concept but are not identified as such. Recombinant "prodrugs" such as engineered anthrax toxin show promise in biological specificity through the conditionally targeting of multiple cellular markers. Conditional targeting is achieved by structural complementation, the spontaneous assembly of engineered inactive subunits or fragments to reconstitute functional activity. These complementing systems can be readily adapted to achieve conditionally bispecific targeting of enzymes that are used to activate low-molecular weight prodrugs. By leveraging strengths from medicinal chemistry, polymer science, and recombinant technology, prodrugs are poised to remain a core component of highly focused and tailored strategies aimed at conditionally attacking complex molecular phenotypes in clinically relevant cancer.

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Prodrugs for Targeted Tumor Therapies: Recent Developments in ADEPT, GDEPT and PMT

Cited by 92 publications

References 0 publications

Colon Cancer–Specific Cytochrome P450 2W1 Converts Duocarmycin Analogues into Potent Tumor Cytotoxins

Colon Cancer–Specific Cytochrome P450 2W1 Converts Duocarmycin Analogues into Potent Tumor Cytotoxins

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

Prodrug Applications for Targeted Cancer Therapy

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