Bioreductive and gene therapy approaches to hypoxic diseases bioreductive and gene therapy approaches to hypoxic diseases jaffar, mohammed. Bioreductive drugs were initially designed to diagnose the presence of, and be toxic towards, the hypoxic cells in tumours. However, much less is known about the impact of sf on the efficacy of cancer therapy through the modulation of drugmetabolizing enzymes. Bioreductive prodrugs can be designed for selective activation under low oxygen conditions typical of many solid tumors. Bcl2 family member proteins pro vs antiapoptotic c.
Pdf creation and screening of a multifamily bacterial. In the last 15 years, the potential of bioreductive drugs has been explored in the clinic with varying levels of success see below. Drugs are given in a variety of dosage forms or drug products such as solids tablets, capsules, semisolids ointments, creams, liquids, suspensions, emulsions, etc, for systemic or local therapeutic activity. Bioreductive activation and drug chaperoning in cobalt. This process was accomplished by using upconversion. A second starting point for sequence selective ligands is an organometallic molecule with chiral properties. These hypoxiaactivated prodrugs can target and kill hypoxic cells, and their effect can extend to include sterilization of surrounding tumor cells when the activated metabolites are sufficiently stable to diffuse beyond their primary site of action. In turn, the laboratory study of natural product drugs commenced approximately 200 years ago, with the puri. Pretomanid tablets used in the combination regimen with bedaquiline and linezolid are contraindicated in patients for. Links to pubmed are also available for selected references.
So basically therapeutic index is a measure of the safety of a drug. A prodrug is a medication or compound that, after administration, is metabolized i. Antitumor activity of the bioreductive prodrug 32nitrophenyl propionic acidpaclitaxel nanoparticles nppaptx nps on mdamb231 cells. Frequent abuse of alcohol and other drugs can lead to addiction, a disease that affects the brain and behavior.
This activation step is catalyzed by a variety of oxidoreductases and differs depending on the bioreductive drug class 18. The chemoprotective properties of sulforaphane sf, derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of xenobioticmetabolizing and antioxidant enzymes. Four new palladiumii complexes with the formula pdl2, where l are quinoxaline2carbonitrile n1,n4dioxide derivatives, were synthesized as a contribution to the chemistry and pharmacology of metal compounds with this class of pharmacologically. The drugs with high ti are considered to be relatively safer drugs. Electrochemically driven supramolecular interaction of quinones and ferrocifens. Assess the differences between classes of biologic diseasemodifying antirheumatic drug dmard therapy. The compound is shortly to enter phase i clinical trials in the united kingdom, and this study describes the preclinical. It can cause or worsen many medical problems and if left untreated can destroy families and lives. Currently, 57% of the drugs approved worldwide can be classified as prodrugs, and approximately 15% of all new drugs approved in 2001 and 2002. Pharmacokinetic studies were performed with the first and.
Sulforaphane preconditioning sensitizes human colon cancer. Hypoxia plays a central role in cancer progression. Glucose transporter glut1 expression correlates with tumor. To date, five distinct classes of bioreactive prodrugs have. Preclinical studies for any bioreductive drug to be effective it will, by definition, require hypoxia, which is primarily found in tumours, and an enzyme or enzymes capable of reducing the drug to a cytotoxic species. Overexpression in two akr1c3negative tumor xenograft models strongly enhanced pr104 antitumor activity. Full text antitumor activity of the bioreductive prodrug 3. Phase i pharmacokinetic and pharmacodynamic study of the. These agents are inactive com pounds that are reduced selectively in hypoxic. Eo9, a derivative of mmc, is an indolequinone bioreductive prodrug that can be activated by dtdiaphorase under hypoxic and normoxic.
These bioreductive compounds are designed to kill cells preferentially within the hypoxia tumor microenvironment. Eo9 is a synthetic indoloquinone which was designed to undergo redox cycling and formation of alkylating intermediates under bioreductive conditions. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. Bioreductive drugs are currently being developed as a means of selectively targeting hypoxic tumour cells. The current status of hif targeted strategies is beyond the scope of this article which focuses on haps, their mechanism of action and recent progress in the preclinical and clinical evaluation of. The p53dependent apoptotic pathway of breast cancer cells.
Combination of radiationactivated prodrugs with ionizing. Modern pharmaceutical drug analysis essentially involves as a necessary integral component even greater horizons than the actual prevalent critical analysis of not only the active pharmaceutical substances but also the secondary pharmaceutical products i. Pharmacological effects, prodrugs definition, examples and. To identify proteins modulated by a low concentration of.
Bioactivation as a model for drug design bioreductive. Full text hypoxiaactivated prodrugs and redoxresponsive. A bioreductive prodrug of cucurbitacin b significantly. Activated pa824 inhibits lipid biosynthesis in a dosedependent manner 14.
As part of a phase i clinical trial, eo9 plasma disposition was evaluated in 20 patients receiving 2. Inactive prodrugs are pharmacologically inactive medications that are metabolized into an active form within the body. Examples undergoing clinical trials includenoxides such as. Glucose transporter glut1 expression correlates with. Get a printable copy pdf file of the complete article 1. Journal of materials chemistry b 2018, 6 17, 25472556. Currently, 57% of the drugs approved worldwide can be classified as prodrugs, and approximately 15% of all new drugs approved in 2001 and 2002 were prodrugs 2,6. The level of oxygenation varies inter and intratumorally, as well as between tumor types 11. Cytotoxic palladium complexes of bioreductive quinoxaline n1,n4dioxide prodrugs.
A preclinical pharmacokinetic study of the bioreductive drug. Cancer research the bioreductive prodrug pr104a is. A preclinical pharmacokinetic study of the bioreductive. Based on individual patient characteristics, construct a treatment and monitoring plan for a patient with ra and, when appropriate, include biologic dmard therapy. These socalled bioreductive prodrugs are constructed in such a way that metabolic reduction leads to the production of a cytotoxic species which can then damage and kill the malignant cells. Bioreductive alkylation is the term used to describe the effect of those compounds which express their mode of biological action as alkylating agents, but do so subsequent to their in vivo reduction. The mechanism of their selective activation in hypoxic. Wilson 1,2, 1 auckland cancer society research centre, school of medical sciences, faculty of medical and health. Two main approaches are being used to eradicate hypoxic cells 1 the use of bioreductive drugs or hypoxiaactivated prodrugs haps and. Targeting the hypoxic fraction of tumours using hypoxiaactivated. Pretomanid tablets, 200 mg, are white to offwhite oval tablets debossed with m on one side and p200 on the other side.
These pro drugs are converted to active intermediates by enzymatic activity either in hypoxic areas of solid tumours sartorelli, 1988 or by increased activity of these enzymes in tumour compared. Embedded with a bioreductive delivery and cleavable system in cancer tissues, cucurbitacin bbased prodrugs 1, 2, and 3 were synthesized and evaluated by in vitro and in vivo experiments. Hypoxia directed drug delivery systems might offer the potential for selective treatment in a whole variety of conditions manifesting chronic hypoxia and inflammation, which are routinely treated using glucocorticoids andor nonsteroidal. Several aziridinylbenzoquinone drugs have undergone clinical trials as potential antitumor drugs. Full text is available as a scanned copy of the original print version. Synthesis and biological properties of bioreductively targeted. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and excretion optimization.
Tumour hypoxia has been pursued as a cancer drug target for over 30 years, most notably using bioreductive hypoxiaactivated prodrugs that. Bioreductive drugs, as an adjunct to any cancer treatment, could potentially fulfil this need. The higher the therapeutic index, the higher the safety of that drug and vice versa. This plethora of effects on tumor biology is orchestrated in. Bioreductive activation has a strong dependence upon cellular oxygen tension, and pro drugs vary in the extent and duration of hypoxia necessary for bioreduction 10. The superoxide radical byproduct of this process is readily detoxified by superoxide dismutase, ensuring bioreductive drugs exhibit minimal toxicity to normal tissues. Clinical advances of hypoxiaactivated prodrugs in combination. Telomeres and pathways in cancer to overcome telomere shortening e.
Until now, five types of bioreactive prodrugs have been shown to be capable of selectively targeting hypoxic cells. Alcohol and drug problem overview the abuse of alcohol and other drugsincluding prescription drugsis common and costly. However, to fully exploit the potential of bioreductive drugs, they will need to be used in combination with other modalities likely to target the proliferating aerobic cells in. These pro drugs are converted to active intermediates by enzymatic activity either in hypoxic areas of solid tumours sartorelli, 1988 or by increased activity. Bioreductive and gene therapy approaches to hypoxic. Bioreductive drugs are targeted to the underoxygenated region of the tumor through activation by specific reductases associated with hypoxia 71.
Benzotriazine dioxide prodrugs for exploiting hypoxia and. Bioreductive prodrugs have been developed to effectively target the hypoxic cell population of tumours. It is clear that the activation of bioreductive drugs is dependent both on the hypoxic tumour microenvironment and the presence of endogenous reductases to metabolise the drugs. Akr1c3 was unable to sensitize cells to 10 other bioreductive prodrugs and was associated with singleagent pr104 activity across a panel of 9 human tumor xenograft models. Such regions generally are resistant to radiation and other oxygenrequiring treatment 14. The bioreductive drugs, aziridinylbenzoquinones, are a class of compounds designed to exploit one of the features of solid tumor biology caused by an inadequate blood supply to the solid tumor. Bioprecursor prodrugs, active metabolites, oxidative activation, glucuronic acid conjugation, bioreductive alkylation. Hypoxia lower than normal oxygen is a characteristic of most solid tumours that results in poor cancer patient prognosis. Drug products can be considered to be drug delivery systems that release.
Once administered, the prodrug is metabolised in vivo into an active metabolite. The synthesis of a crgdyk targeted sn38 prodrug with an. However, the rapid onset of resistance to most antiinfective drugs diminishes their effectiveness considerably and requires a constant supply of new drugs for the effective. Bioreductive drugs undergo metabolic reduction to generate cytotoxic metabolites. Antitumor activity of the bioreductive prodrug 3 2 nitrophenyl propionic acidpaclitaxel nanoparticles nppaptx nps on mdamb231 cells. A central concept in targeting tumor hypoxia is that of bioreductive prodrugs. Hallmarks of cancer and how they could affect 45 rs of radiobiology ii. Bioreductive prodrugs have been developed to preferentially. Aq4n 1,4bis2dimethylamino n oxideethylamino5,8dihydroxyanthracene9,10dione is in a class of bioreductive agents incorporating the aliphatic n oxide functionality and is well documented as a very effective enhancer of radiotherapy and chemotherapy.
An example of redox activation of bioactive compounds volume. Cobalt pro drugs built upon the tris2pyridylmethylamine ligand scaffold with varying charge were investigated for distribution and activity in a 3d tumor spheroid model by laser ablation inductively coupled plasma mass spectrometry laicpms and mri. There are four main classes of bioreductive drugs currently undergoing clinical or preclinical evaluation in the treatment and. Routine exams provide piece of mind for our patients, as well as preventative care to ensure a desired level of health. Because of this specificity, bioreductive drugs have enormous potential to contribute to modern cancer therapy. Electrochemically driven supramolecular interaction of. The experimental development of bioreductive drugs and. Bioreductive drugs that are activated in response to this hypoxic environment are an attractive strategy for therapy with anticipated lower harmful side effects in normoxic healthy tissue. Preclinical efficacy of the bioreductive alkylating agent. Methods now exist for the identification of human tumors that contain significant numbers of hypoxic cells and are thereby suitable for treatment with bioreductive drugs to eliminate this refractory cell population. Formaldehyde is a good disinfectant, unfortunately, high doses are toxic to humans so it cannot be used directly in drugs. The bioreductive prodrug pr104a is activated under.
This process is facilitated by bioreductive enzymes and the lower oxygen conditions present in solid tumours compared to normal tissues. The potential for cobaltiii complexes in medicine, as chaperones of bioactive ligands, and to target tumours through bioreductive activation, has been examined over the past 20 years. Strong hypoxia created by upconversion photodynamic therapy uc. A sequential enzymeactivated and lighttriggered pro prodrug nanosystem for cancer detection and therapy. Fda approved 31 new biotechnological drugs and by august 2009 a further 12 new biotechnological drugs were approved e. Preclinical efficacy of the bioreductive alkylating agent rh1. Preferential killing of cancer cells can occur in one of two ways or via of the combination of the two. Dense tumors are resistant to conventional chemotherapies due to the unique tumor microenvironment characterized by hypoxic regions that promote cellular dormancy. A prodrug must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent. Four classes of compound have been developed since this concept was first proposed. Hypoxiaactivated prodrugs of the kdac inhibitor vorinostat. 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. We also discuss the lessons learnt from past drug design and the future of this field. Natural products have played a pivotal role in antibiotic drug discovery, with most antiinfective drugs being derived from a natural product or natural product lead.
Pdf clinical advances of hypoxiaactivated prodrugs in. The bioreductive compound of bistype naphthoquinone synthesized in our laboratory, 2aziridin1yl3223aziridin1yl1,4dioxo1,4dihydronaphthalen2ylthioethoxyethyl. In a tissue microarray tma survey of akr1c3 expression in surgical samples, we show that akr1c3 is highly expressed in some human tumors. The bioreductive approach is perhaps the most advanced, and uses changes in intracellular redox enzyme concentrations to activate otherwise inactive pro drug molecules inside cancer cells by a. Bioreductive drugs are theoretically well suited to improving selectivity through an enzymedirected approach to tumour targeting and the in vitro and in vivo features of rh1 fulfil some but not all the required features, namely that the agent is a good substrate for dtd and this enzyme is highly overexpressed in some tumours. It has to be broken down by bacteria in the colon into two products 5aminosalicylic acid 5asa and.
Methenamine is a stable, solid prodrug form of formaldehyde when it comes into contact with acidic urine it becomes formaldehyde and ammonia but over time the ammonia builds up and will increase ph for the bladder and utis. Hay 1,2, hong nam shin 1, way wua wong 1, wan wan sahimi 3, aaron t. The idea of bioreductive anticancer agents, statts with the fact that tumours receive less blood and hence less oxygen than normal tissue. Johns university, jamaica, new york 11439 received december 27, 2002. Then, beginning about 500 years ago, information on medicinal plants began to be documented in herbals. Full text antitumor activity of the bioreductive prodrug.
Sep 05, 2018 antitumor activity of the bioreductive prodrug 3 2 nitrophenyl propionic acidpaclitaxel nanoparticles nppaptx nps on mdamb231 cells. Bioreductive prodrugs for cancer therapy springerlink. Phase i human cancer clinical trials of the sodium ca4 phosphate prodrug 2. Prodrugs are usually designed to improve oral bioavailability, with poor.
Bioreductive activation has a strong dependence upon cellular oxygen tension, and pro drugs vary in the extent and duration of hypoxia necessary for bioreduction. Both compounds are pro drugs that require bioreductive activation and show no crossresistance to other frontline tb drugs. Hypoxiaresponsive cobalt complexes in tumor spheroids. Bioreductive alkylation naturally occurring quinones as. Local hypoxia in tumors is an undesirable consequence of photodynamic therapy pdt, which will lead to greatly reduced effectiveness of this therapy. One example of targeted cancer therapeutics is hypoxiaactivated prodrugs haps, also known as bioreductive prodrugs. In this work, several bioreductive prodrugs of cub were designed to reduce toxicity to normal cells while maintaining the cytotoxic effect to cancer cells. Two potentially complementary approaches to improve the anticancer strategy genedirected enzyme prodrug therapy gdept are discovery of more efficient prodrugactivating enzymes, and development of more effective prodrugs. Instead of administering a drug directly, a corresponding prodrug might be. Drugs are substances intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. Despite this, chemical properties such as reduction potential and carrier ligands required for optimal tumour targeting and drug delivery have not been optimised.