The role of hypoxiaactivated prodrugs in cancer therapy. For proofofconcept smept, we use surface adhered microstructured physical. A prodrug is then given, which is converted to a cytotoxic drug selectively in the tumor. Ten patients with colorectal carcinoma expressing carcinoembryonic antigen received antibodydirected enzyme prodrug therapy with a5b7 fab. Directed enzyme prodrug therapy vdept and gene prodrug activation therapy gpat. Polymerdirected enzyme prodrug therapy is a twostep antitumor approach that uses a combination of a polymeric prodrug and a polymerenzyme conjugate to generate selective cytotoxicity. A prodrug program research operating plan rop prioritizing activities on. Also shown in table table1 1 are two parameters that are useful in comparing the different gdept systems.
Prodrugs for site specificity sitespecific drug delivery helps for accurate and direct effects at the site of action without subjecting the remaining tissues to significant levels of the active agent. In this system, a functional transgene expression cassette is created by. Directed enzyme prodrug therapy dept uses enzymes artificially introduced into the body to convert prodrugs, which have no or poor biologically activity, to the active form in the desired location within the body. Inactive prodrugs are pharmacologically inactive medications that are metabolized into an active form within the body. Prodrugactivating systems in perspective suicide gene therapy. The presentation describes the study of prodrugs in problem related to bioavailability and elegance of formulation. When administered in the body it was metabolized by the. Prodrugs do they have advantages in clinical practice. Strategies for enzymeprodrug cancer therapy clinical cancer. Enzyme which can activate the prodrug is administered in the first step. John toth, product manager for cooper lasersonics, in 1981 wrote a white paper on early clinical argon dye lasers for their use in photodynamic therapy.
Enzymeactivated prodrug therapy enhances tumorspecific. While confining prodrug activation to the tumor tissue and thus rendering chemotherapy more specific, the viral infection potentially enhances the susceptibility of tumor cells to drug. A prodrug is a medication or compound that, after administration, is metabolized i. Several tumorspecific transription responsive elements tres have. Indeed, tumor hypoxia can promote resistance to apoptosis, encourage hypermutation by inhibiting dna repair, alter cell metabolism to favor cell growth, upregulate angiogenesis, enhance local invasiveness, drive metastatic spread, and provide a sanctuary for cancer stem cells. Prodrug needs to be converted to 5asa onset of action 3 to 4 weeks absorption 1015% in small intestine intolerance is very common due to sulfapyridine moiety nv, dyspepsia, and headache adverse effects allergic reactions, pancreatitis, hepatotoxicity, interstitial nephritis, hemolytic and megaloblastic anemia. Aug 15, 2015 schematic presentation of genedirected enzyme prodrug therapy gdept. Although a variety of oneelectron or twoelectron oxidoreductases are known to be involved in prodrug reduction, the frequency and amplitude of their expression in human tumors is poorly defined. Preclinical and clinical studies of cyp genedirected enzyme prodrug therapy have been focused on anticancer prodrugs activated by cyp2b enzymes. To address this issue and move our concept forward, we aimed to improve the ratelimiting step of prodrug activation by ctsl fig. Synthesis and preclinical evaluation of a highly improved.
Schematic presentation of genedirected enzyme prodrug therapy gdept. Schematic presentation of genedirected enzyme prodrug therapy. Prontosil was found to be effective against microorganisms only in vivo, and not in vitro. Thus, in a preliminary study of this approach, administration of the previously mentioned doxorubicin conjugate pk1 was followed by the administration of a conjugate of the proteolytic enzyme cathepsin b, present in all mammalian cell lysosomes. Diethylstilbestrol diphosphate was originally designed for sitespecific delivery of diethylstilbestrol to prostatic carcinoma tissue. As a case in point, tumor microenvironment tme, which is characterized by acidic ph, elevated temperature, and overexpressed proteases, provide a useful target for triggering the activation of prodrugs. Introduction various approaches to enhance efficacy of the drug hard and soft drugs prodrugs classification of prodrugs considerations in the design of prodrugs strategies in the design of prodrugs applications of prodrugs prodrug based novel drug delivery approaches conclusion references download the powerpoint by liking us on facebook. In pdt, visible or nearinfrared light is used to photoactivate inert prodrugs to cytotoxic agents. Prodrug applications for targeted cancer therapy ncbi nih.
Both the potential for activation and the degree of activation depend on the cell lines sensitivity to the. New approach to targeted prodrug therapy the lancet. Phenacetin, a proprodrug toxification activation toxification hugo kubinyi. Adenoviruses ads that selectively replicate in tumor cells have shown promising preliminary results in clinical trials, especially in combination with chemotherapy. Although the original prodrug boclysacpuromycin show promise as a selective cancer therapy, its requirement of relatively high dosage could be a potential issue for the clinical applications. In antibodydirected enzyme prodrug therapy, an enzyme conjugated to an antitumor antibody is given i. The latter approach, known as genedirected enzyme prodrug therapy gdept 1, 2 or virusdirected enzyme prodrug therapy vdept 3, may be used in isolation or combined with other strategies, such as. Enzymeactivating prodrug therapy is a twostep approach. In this work, we report the synthesis and biological assessment of the nearinfrared nir prodrug dcmsppt and its amphiphilic copolymer mpegdspeencapsulated nanoparticles. A small molecule that reacts with a specific antibody but cannot induce the formation of antibodies unless it is bound to a carrier. Nitroheterocyclic prodrugs have been used to treat trypanosomal diseases for more than 40 years. Selective cancer targeting with prodrugs activated by. The gene therapy approach most commonly used in clinical trials for brain tumors is genedirected enzyme prodrug therapy also known as suicide gene therapy.
Several tumorspecific transription responsive elements tres have been used. The basic aim of prodrug design is to mask undesir able drug properties, such as low solubility in water or lipid membranes, low target selectivity, chemical in stability, undesirable taste, irritation or pain after local administration, presystemic metabolism and toxicity 54, 70, 74. In this report, we detail substrate mediated enzyme prodrug therapy smept as a novel approach in drug delivery which relies on enzymefunctionalized cell culture substrates to achieve a localized conversion of benign prodrugs into active therapeutics with subsequent delivery to adhering cells or adjacent tissues. Potentiation of methoxymorpholinyl doxorubicin antitumor. Instead of administering a drug directly, a corresponding prodrug might be. The prodrug concept the prodrug concept is illustrated in figure 1. Consequently, a prodrug of a cytotoxic agent could be directed to tumor cells if either of these enzymes were important to the prodrug activation process. Prodrug definition of prodrug by medical dictionary. Prodrug design improves bioavailability, aqueous solubility, palatability and also gives protection against fast metabolism 12 16. Abstract gene therapy of cancer is a novel approach with the potential to selectively. One of the targeting methods is enzy me activated prodrug therapy where the nontoxi c prodrug is converted t o the active drug in the tumor tissue 37. The prodrug approach gained attention asa technique for improving drug therapy in the early 1970s. In vivo bioactivation of prodrugs by enzymatic andor chemical.
As a case in point, tumor microenvironment tme, which is characterized by acidic ph, elevated temperature, and overexpressed proteases, provide a useful target for triggering the activation of. Numerous prodrugs have been designated and developed since then to overcome pharmaceutical and pharmacokinetic barriers in clinical drug application, such as low oral drug absorption, lack of site specificity, chemical stability, toxicity and poor. Many chemotherapy drugs for cancer lack tumour specificity and the doses required to reach therapeutic levels in the tumour are often toxic to other tissues. It represents the maximum possible efficiency of a given enzymeprodrug. Ppt prodrugs ii powerpoint presentation free to view id.
It involves the insertion of a gene encoding a drugmetabolizing enzyme into cells and the systemic administration of a prodrug. After systemic injection of the prodrug, cytotoxic activation takes place at the target only. The activation of prodrug may occur at any time during absorption, distribution or metabolism. Prostate cancer is a leading cause of cancerrelated death and morbidity in men in the western world. Paradoxically, it is also an attractive therapeutic target, because severe hypoxia occurs only in solid tumour tissue. Based on the synergistic effect of viral and cytostatic therapy, ads appear to be particularly well suited for the delivery of prodrug activating enzymes. In some cases, this can result in oxygenindependent prodrug activation. An immunoglobulin protein produced by the immune system in response to the invasion of a foreign substance hapten. Tumour hypoxia, a deficiency of oxygen due to an inefficient vasculature, is a limiting factor in both the radiotherapy and chemotherapy of solid tumours. Virusdirected enzyme prodrug therapy vdept vdept is the term given to the use of a virus to deliver the gene for gdept. Gene for foreign enzyme is transfected to tumor cells, which express the enzyme to activate the systemically administered prodrug 41. To address this issue and move our concept forward, we aimed to improve the.
Tk inhibitors can block tyrosine kinase reversibly or irreversibly. This plethora of effects on tumor biology is orchestrated in. About 57% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Hypoxia plays a central role in cancer progression. Once administered, the prodrug is metabolised in vivo into an active metabolite. Prodrug is a common approach for achieving tissuespecific drug delivery and reducing toxic side effects. In this work, we report the synthesis and biological assessment of the nearinfrared nir prodrug dcms ppt and its amphiphilic copolymer mpegdspeencapsulated nanoparticles. Genetic prodrug activation therapy gpat induces the selective expression of a drugmetabolizing enzyme for activation of prodrug into a toxic moiety using the known transcriptional differences between normal and tumor cells 33, 34. Bioprecursor prodrugs rely on oxidative or reductive activation reactions unlike the hydrolytic activation of carrierlinked prodrugs.
Genetic prodrug activation therapy clinical trial for breast cancer to date, only one phase i clinical trial using gpat as a potential treatment for breast cancer has been described 27. The purpose of the trial was to test the safety and efficacy of tumourspecific expression of the cd gene driven by the erb b2 promoter. Selective cancer targeting with prodrugs activated by histone. Jan, 2014 contents of the powerpoint on prodrugs include. Suicidegene therapy suicidegene therapy is based on transducing cells with a gene that converts a prodrug into a cytotoxic agent there is a substantial bystander effect. Catalytic antibodies and their use as therapeutic agents. Hypoxic cells can be exploited for therapy by nontoxic, hypoxiaactivated prodrugs.
Gdept is a suicide gene therapy in which the enzyme required for prodrug conversion is produced within the target cell, using a gene delivered to it by gene therapy. The german physician friedrich meyerbetz performed studies of photodynamic therapy with porphyrins in 19 by testing the effects of hematoporphyrin use on his own skin. Ppt prodrugs ii powerpoint presentation free to view. Gshactivated nir fluorescent prodrug for podophyllotoxin. The prodrug is converted to a cytotoxic agent by the action of the expressed enzyme. Based on the synergistic effect of viral and cytostatic therapy, ads appear to be particularly well suited for the delivery of prodrugactivating enzymes. Enzyme prodrug therapy an overview sciencedirect topics. In this system, a functional transgene expression cassette is. Is a onestep therapy, only the prodrug is administered. Other targeted prodrug therapies make use of a variety of mechanisms for getting drugs to act on tumour cells, including antibody targeting and gene therapy. Tumor progression is dependent on functioning androgen receptor signaling, and. The first parameter is defined as the ratio of ic 50 s of the prodrug and of the active drug in a nontransfected control tumor cell line. Here, we describe a system that combines the antitumor synergy of ads and chemotherapeutic agents with the benefits of enzymeactivated prodrug therapy. But taylor believes these approaches have disadvantages because they require a knowledge of the biochemistry of the disease.
When an adequate differential exists between the targeted cell and endogenous tissue, nontoxic prodrug is administered and is subsequently converted into its toxic form within the target cell. Example prodrug handles and subsequent functional prodrugs 4. During its activation stage, the prodrug might consume a vital cell constituent such as glutathione leading to its depletion. A prodrug is a pharmacological substance that is administered in an inactive or significantly less active form. An ideal prodrug for gdept should be nontoxic or minimally toxic prior to activation by enzyme but highly toxic after enzymatic activation. Oncolytic adenovirusmediated therapy for prostate cancer.
Theranostic prodrug therapy enables the targeted delivery of anticancer drugs with minimized adverse effects and realtime in situ monitoring of activation of the prodrugs. May 01, 2000 the degree of activation is defined as the ratio of the ic 50 of the prodrug in the nontransfected cell line to the ic 50 of the prodrug in the transfected or infected derivative of the cell line that expresses the activating enzyme. The prodrug can be activated by a non enzymatic process such as hydrolysis. Prodrug concept prepared by, janet thomas i mpharm. Genetic prodrug activation therapy anne rigg and karol sikora genetic prod rug activation therapy shows promise as a therapeutic option for the treatment of cancer as well as a variety of other diseases. Tumor progression is dependent on functioning androgen receptor signaling, and initial. Genetic prodrug activation therapy shows promise as a therapeutic option for the treatment of cancer as well as a variety of other diseases. Nov 14, 2008 preclinical and clinical studies of cyp genedirected enzyme prodrug therapy have been focused on anticancer prodrugs activated by cyp2b enzymes, which have low endogenous expression in human. These are designed for direct activation or recognition by a tumortissue associated factor.
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