Rationale for clinical evaluation of tarloxotinib bromide, a. Development of inhibitors targeting hypoxiainducible. Bowyer, cressida, lewis, andrew, lloyd, andrew, phillips, gary and macfarlane, wendy 2017 hypoxia as a target for drug combination therapy of liver cancer anti cancer drugs, 28 7. Pdt, which combines a photosensitizer and photons to produce cytotoxic reactive oxygen species, has been established as an effective cancer treatment, but has yet to become mainstream. Such information will be of importance for the research and development of cmyctargeted drugs. Hypoxia activated prodrugs haps are prodrugs that target regions of tumor hypoxia within tumor cells. Blood tests may be done to measure blood gases, such as oxygen, acids, and carbon dioxide. Marchal 2,3,4,5,6 and houria boulaiz 2,3,4,5,6, 1 department of physical chemistry, faculty of pharmacy, university of granada, 18071 granada, spain.
Th302 exhibits activity against a range of cell lines, especially those with deficiency in homologydirected dna repair, brca1, brca2, or fanca. Hypoxiaactivated nanomedicines for effective cancer. Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. In contrast, in the hypoxic tumor microenvironment, the o 2 level is 0. Only a small proportion of cells in a solid tumour are wad is at the auckland cancer society research centre, faculty of. In combination therapy, the hypoxia activated prodrug and another anticancer agent or radiation therapy may be administered within the same 24hour period, and administration of the hypoxia activated prodrug may be completed. Rationale for clinical evaluation of tarloxotinib bromide, a hypoxiaactivated egfrher2 inhibitor, in nsclc and squamous cell carcinoma of the headneck or skin patterson, adam1 1cancer society research centre, auckland tarloxotinib bromide tarloxitinib, th4000, previously pr610 is a prodrug that releases a potent. Prodrugs activated by 2nitroimidazole reduction demonstrated up to 400fold enhanced. Hepatocellular carcinoma hcc is the third most frequentcause of cancer deaths worldwide. Data sources include ibm watson micromedex updated 28 feb 2020, cerner multum updated 2 mar 2020, wolters kluwer updated. Tumor hypoxia is recognized as a major contributing factor in the progression of prostate cancer. During the growth of a solid neoplasia, the tumor microenvironment tm undergoes biochemical changes that include depletion of glucose, bicarbonate, o 2 i.
Treatment of cancer using hypoxia activated prodrugs the lens. Synthetic and biological investigations into hypoxiaactivated antitumour codrugs nicholas kirk university of wollongong unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the university of wollongong. May 21, 2015 th302mediated in vitro and in vivo anti tumor activities were greatly enhanced by the addition of chk1 inhibitors. Hepatobiliary cancer hypoxiainducible factor hif1 is a transcription factor playing a central part in. Hypoxia is associated with insufficient response to standard therapy.
Jci hypoxia, angiogenesis, and metabolism in the hereditary. In combination therapy, the hypoxiaactivated prodrug and another anti cancer agent or radiation therapy may be administered within the same 24hour period, and administration of the hypoxiaactivated prodrug may be completed. While oxygen is critical to the continued existence of complex organisms, extreme levels of oxygen within a system, known as hypoxia low levels of oxygen and hyperoxia excessive levels of oxygen, potentially promote stress within a defined biological environment. The transcription factor that orchestrates responses to hypoxia is hypoxia inducible factor 1 hif1. The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications.
A strong argument therefore exists for assessing the hypoxic fraction of tumours, prior to patient treatment. The preclinical data presented in this study support a new approach for the treatment of p53deficient hypoxic cancers by combining chk1 inhibitors with the hypoxiaactivated prodrug th302. A series of achiral hypoxia activated prodrugs were synthesized on the basis of the dna crosslinking toxin of the prodrug, ifosfamide. Potent and highly selective hypoxiaactivated achiral phosphoramidate mustards as anticancer drugs jianxin duan, hailong jiao, jacob kaizerman, timothy stanton, james w. Mechanisms of hypoxiamediated immune escape in cancer. The consequences of tissue hypoxia, a result of a defective oxygen supply, vary in response to the gravity, extent and.
Acps anticancer peptides, or cationic amps with anticancer properties, selectively. This plethora of effects on tumor biology is orchestrated in. Hypoxiaactivated nanomedicines for effective cancer therapy. Definition of hypoxiaactivated prodrug th4000 nci drug. Haps may offer the potential, alone and in combination with conventional chemotherapy, of improving cancer therapy. Clinical cancer progression is also associated with the development of tumor hypoxia, which is mechanistically linked to the acquisition of malignant phenotypes in cancer cells. Tumour hypoxia has been pursued as a cancer drug target for over 30 years, most notably using bioreductive hypoxiaactivated prodrugs that target antineoplastic agents to lowoxygen tumour compartments. We sought to reexplore the hypoxiaactivated phosphoramidate bis alkylator prodrug area with the goal of increasing the selectivity of the prodrugs for hypoxic cells and improving the therapeutic index. Reconsidering azobenzene as a component of smallmolecule.
A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. The consummation of molecular oxygen could increase the local hypoxia level in the progress of goxinvolved cancer therapy. Pdf antimicrobial peptides with selective antitumor mechanisms. Spices for prevention and treatment of cancers jie zheng 1, yue zhou 1, ya li 1, dongping xu 1. Hypoxia plays a central role in cancer progression. Another promising clinical stage nitro compound is th302, a 2nitroimidazolebased nitrogen mustard prodrug. Haps work by killing cancer cells in lowoxygen patches of a tumor that are. It is believed that tumor hypoxia contributes significantly to treatment failure and relapse among cancer patients because cells in the hypoxic zones of solid tumors resist.
Rationale for clinical evaluation of tarloxotinib bromide. Initially, these early studies focused primarily on enzymeactivated prodrugs in a process called bioreductive activation under aerobic conditions, but this concept was extended. The oldest anticancer prodrug, cb1954, has shown little therapeutic effects but sn23862 showed potential. Hypoxia and oxidative stress in breast cancer tumour. Advances in nanomedicine for cancer starvation therapy. Hypoxia in tumor cells is characterized by a lack of oxygen resulting from reduced blood supply to the surrounding tissue, and is a common characteristic of solid tumors as a consequence of rapid. Prospects for hypoxiaactivated anticancer drugs volume. The transcription factor that orchestrates responses to hypoxia is hypoxiainducible factor 1 hif1. One therapeutic approach being developed for the treatment of cancer is. Hypoxiaactivated prodrugs in the treatment of advanced. Multimodal targeting of tumor vasculature and cancer stemlike cells in sarcomas with vegfa inhibition, hif1. Photothermalhypoxia sequential activatable phasechange. Although hypoxia is an important driver of tumor invasion and metastasis, as well as resistance to therapy, there is limited knowledge on the contribution of hypoxia to tumor cell escape from destruction by innate and adaptive immune effector.
Potent and highly selective hypoxiaactivated achiral. Targeting hypoxic prostate tumors using the novel hypoxia. Hence, many efforts have been made to study hypoxia activated nanomedicines that are aimed at increasing drug efficiency and reducing systemic toxicity 45,46. The accessibility of breast carcinomas has enabled the use of polarographic o 2 needle electrodes to assess tumour oxygenation. Upon administration, the hypoxiaactivated prodrug th4000 is activated in the hypoxic cells within tumors into an irreversible panher inhibitor via a mechanism of action not yet fully elucidated. Tumor hypoxia is feature of locally advancing solid tumor and also considered as potential therapeutic challenge. Therefore, haps in combination with radiation therapy could present a unique therapeutic combination whereby the two should yield complementary killing, as hypoxia activated drugs kill the tumor cells that are resistant to ionizing radiation.
A firstinclass hypoxiaactivated tyrosine kinase inhibitor smaill, jeff 1,2, lu, guoliang 1, lee, ho 1, abbattista, maria1, guise, christopher 1, hsu, huailing 1, jaiswal, jagdish 1, jamieson, stephen 1, ashoorzadeh, amir 1, anderson, robert 1 and patterson, adam 1, 2 1 auckland cancer society research centre, the university of auckland, auckland. Preclinical studies demonstrate that in vivo aq4n enhances the anti tumour effects of radiation and chemotherapeutic agents with a dosemodifying factor of approximately 2. Nontoxic drugs which can only be activated in hypoxic regions hypoxiaactivated prodrugs therefore offer the possibility of specific systemic treatment for solid tumours, including metastases. Hypoxia in solid tumors and the affected bone marrow of hematologic malignancies is a prevalent feature of cancer. Hypoxia occurs quite early in tumour growth, so that micrometastases greater than about 1 mm in diameter can also be targeted. The aim of this study was to assess the effects and mechanism of action of a no. Hypoxiaactivated prodrugs haps could help prevent drug resistance in a subtype of lung cancer, says a new study. A new appreciation of the critical importance of the extravascular diffusion of the parent prodrug from the blood vessels to the remote hypoxic cells, and the backdiffusion of the activated cytotoxin from the hypoxic cells to surrounding tumor cells, is now guiding drug design in this area. Hypoxia as a target for drug combination therapy of liver. Hypoxiaactivated prodrugs haps are prodrugs that target regions of tumor hypoxia within tumor cells. The anticancer agent pr104 is currently in phase ii clinical trials. To understand the role of hypoxia in prostate tumor progression and to evaluate the ability of the novel unidirectional hypoxiaactivated prodrug oct1002 to enhance the antitumor effect of bicalutamide. Initially, these early studies focused primarily on enzyme activated prodrugs in a process called bioreductive activation. As a response to hypoxia and nutrient deficiencies, cells activate angiogenesis, that is the development of.
Tissue hypoxia, owing to an inadequate blood supply, is a common feature of most solid tumours, and breast carcinoma is no exception. Such studies have demonstrated an overall lower median po 2 level in malignant tumours compared with benign tumours. These factors decrease the therapeutic efficacy of anticancer drugs and. Hypoxiainducible factors as an alternative source of treatment. Jan 25, 2016 paradoxically, it is recognised as a highpriority target and one of the therapeutic strategies designed to eradicate hypoxic cells in tumours is a group of compounds known collectively as hypoxia activated prodrugs haps or bioreductive drugs. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxiaadapted cancer cells. Us20202716a1 treatment of cancer using hypoxia activated. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The aim of this work is to show that targeting hif1 with combined drug therapy presents an opportunity for improving outcomes for hcc treatment. Macrophage responses under hypoxic conditions a drug. The development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years. In combination therapy, the hypoxiaactivated prodrug and another anticancer agent or radiation therapy may be administered within the same 24hour period, and administration of the hypoxiaactivated prodrug may be completed. Enhancement of hypoxiaactivated prodrug th302 antitumor.
Hypoxia, a characteristic of many solid cancers, develops from an imbalance between oxygen consumption and oxygen supply. Hepg2 cells were cultured under normoxic and hypoxic conditions. In combination therapy, the hypoxiaactivated prodrug and another anti cancer agent or radiation therapy may be administered within the same 24hour period, and administration of the hypoxiaactivated prodrug may be completed prior to beginning administration of the other anticancer agent or radiation therapy. Hypoxia and oxidative stress in breast cancer tumour hypoxia. Pankaj dinkar patil, raju tayade department of pharmaceutical sciences and technology, ict mumbai, maharashtra pankaj. Cancer can be treated by administration of a hypoxia activated prodrug, such as th302, alone or in combination with other anticancer agents andor radiation therapy. This promoted hypoxic microenvironment was also employed to activate the hypoxiaactivated prodrugs and amplify their antitumor activity, 30, 33. The role of hypoxiaactivated prodrugs in cancer therapy. The concept of hypoxiaactivated prodrugs arose largely from the seminal work on quinonebased derivatives of mitomycin c by alan sartorelli in the early 1970s. The consequence of increased expression of pgp is a reduction in cellular sequestration of multiple anti cancer drugs, and it is likely that this pathway is correlated with tumor resistance to topoisomerase iitargeted drugs tredan et al. This is an important consideration when developing physiologically relevant human cell based assay to screen small molecules for antitumor effects on macrophages. Reconsidering azobenzene as a component of smallmolecule hypoxia mediated cancer drugs.
Pdf tumorpenetrating nanoparticles for enhanced anticancer. Jan 25, 2016 two main approaches are being used to eradicate hypoxic cells 1 the use of bioreductive drugs or hypoxiaactivated prodrugs haps and 2 molecularly targeted drugs aimed at exploiting biochemical responses to hypoxia, particularly hif pathways. N2 hypoxia is a known feature of aggressive solid tumors as well as a critical hallmark of the niche in aggressive hematologic malignances. Drug resistance and increased mortality of patients are associated with the overexpression of hypoxiaactivated factor1. Full text hypoxiaactivated prodrugs and redoxresponsive. Hypoxia in tumor cells is characterized by a lack of oxygen resulting from reduced blood supply to the surrounding tissue, and is a common characteristic o. Repurposing drugs in oncology redo nitroglycerin as an anticancer agentsupplementary material introduction the following drugs warrant further investigation in combination with nitroglycerin ntg and existing standard of care chemotherapy and radiotherapy protocols, both in preclinical studies and potentially in clinical trials. Evofosfamide is a hypoxiaactivated prodrug that selectively targets the hypoxic regions of solid tumors. Nontoxic drugs which can only be activated in hypoxic regions hypoxia activated prodrugs therefore offer the possibility of specific systemic treatment for solid tumours, including metastases. 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. Blood tests may also be used to find the cause of your hypoxia.
Hypoxiainducible factors hifs are the key factors that control hypoxiainducible pathways by regulating the expression of a vast array of genes involved in cancer progression and treatment resistance. Tumor hypoxia is considered an important factor in metastasis and disease relapse. Cancer can be treated by administration of a hypoxiaactivated prodrug, such as th302, alone or in combination with other anticancer agents andor radiation therapy. Therefore, selective induction of apoptosis in cancer cells but not normal cells seems feasible. Hifs, mainly hif1 and 2, have become potential targets for developing novel cancer therapeutics. Synthetic and biological investigations into hypoxia. A proprietary, hypoxiaactivated prodrug with potential antineoplastic activity. Reduction by oneelectron oxidoreductases in hypoxic cells leads to fragmentation of the 2nitroimidazole trigger unit and release of bromoisophosphoramide mustard. Frontiers hypoxiamodified cancer cell metabolism cell. The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Repurposing drugs in oncology redonitroglycerin as an. Cancer therapy, chemotherapy, drug resistance, hypoxia, tumor microenvironment. An important aspect of malignant progression is the acquired ability of tumor cells to avoid recognition and destruction by the immune system immune escape. This study demonstrates a new intracellular photochemotherapy nanosystem that coencapsulates photosensitizers and hypoxia activated drugs to enhance the overall anticancer effect precisely and efficiently, thus holding great promise for cancer treatments in the future.
This study provides the first evidence that a novel unidirectional hypoxia activated prodrug, oct1002, effectively targets hypoxic tumor cells. A series of achiral hypoxiaactivated prodrugs were synthesized on the basis of the dna crosslinking toxin of the prodrug, ifosfamide. The original article describes how, cancer remains a major global malaise requiring the advent of new, efficient and lowcost treatments. Cells in the hypoxic tumor microenvironment are more resistant to radiotherapy and to most antiproliferative cancer drugs, and also acquire a more malignant and metastatic phenotype.
This promoted hypoxic microenvironment was also employed to activate the hypoxia activated prodrugs and amplify their antitumor activity, 30, 33. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Thp1 u937 u937 thp1 a172 a549 in hypoxia, cancer cell lines altered their. The hypoxiaselective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Synthetic and biological investigations into hypoxiaactivated anti tumour codrugs nicholas kirk university of wollongong unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the university of wollongong. The effect of oct1002 on prostate cancer cells lncap, 22rv1, and pc3 was measured in normoxia and hypoxia in vitro. In order to survive the hypoxic microenvironment, cancer cells activate. Therefore, haps in combination with radiation therapy could present a unique therapeutic combination whereby the two should yield complementary killing, as hypoxiaactivated drugs kill the tumor cells that are resistant to ionizing radiation. The hypoxia selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Treatment of cancer using hypoxia activated prodrugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. The standard of care for intermediate hcc is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. In contrast, a drug that is preferentially cytotoxic in hypoxic cells would display the opposite trend. Resistance to anticancer drugs can be acquired by several mechanisms within neoplastic cells, defined as 1 alteration of drug.
Hypoxia in tumors is a predictor of both resistance to chemotherapy and of a metastaticaggressive form of cancer, and as a result, development of cancer therapies which target hypoxia is of vital importance. Preclinical studies demonstrate that in vivo aq4n enhances the antitumour effects of radiation and chemotherapeutic agents with a dosemodifying factor of approximately 2. Pdf poor tumor penetration is a major challenge for the use of. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. Use of threedimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxiatargeted anticancer drugs. Hypoxiaactivated prodrugs are commonly used in clinical trials with favorable prospects, while redoxresponsive nanocarriers are currently at the experimental stage. However, cancer cells are often reliant on these molecular aberrations for survival. Targeting the hypoxic fraction of tumours using hypoxiaactivated. Prospects for hypoxiaactivated anticancer drugs bentham. A pulse oximeter is a device that measures the amount of oxygen in your blood. Repurposing drugs in oncology redo nitroglycerin as an anti cancer agentsupplementary material introduction the following drugs warrant further investigation in combination with nitroglycerin ntg and existing standard of care chemotherapy and radiotherapy protocols, both in preclinical studies and potentially in clinical trials.
Despite the wellestablished role of hypoxia in tumor cell. Upon administration, the hypoxia activated prodrug th4000 is activated in the hypoxic cells within tumors into an irreversible panher inhibitor via a mechanism of action not yet fully elucidated. Conclusive research has shown that regions of acutechronic hypoxia, which exist within the majority of solid tumours, have a profound influence on the therapeutic outcome of cancer chemotherapy and radiotherapy and are a strong prognostic factor of disease progression and survival. The occurrence of hypoxic cells in solid tumors, and their resistance to radiotherapy and many chemotherapeutic drugs, has engendered an interest in nontoxic prodrugs that can be activated selectively under hypoxic conditions. Hypoxiainduced changes in ion homeostasis, erythropoiesis, angiogenesis, pro liferation and differentiatio n. In 1996, giaccia showed that the hypoxia microenvironment could select for tumors, because cells that lacked p53 overran p53 wildtype cells in an experimental hypoxic environment.
These drugs are inactive prodrugs that require enzymatic activation. Combination of hypoxia activated drugslinkers with nanomedicine could be harnessed for enhanced tumor specific delivery of different anticancer agents to the hypoxic tumor microenvironment. Hypoxia as a target for drug combination therapy of liver cancer. Resistance to anti cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as 1 alteration of. Auckland cancer society research centre, school of medical sciences, the university of auckland,private bag 90219, auckland, new zealand. Targeted induction of apoptosis for cancer therapy.
Targeting the hypoxic fraction of tumours using hypoxia. The devised prodrug consists of an anticancer drug floxuridine fdu. Hypoxia occurs because of an imbalanced oxygen demand by cancer cells that are rapidly dividing and is a common characteristic of many malignant solid tumors. It causes solid tumor resistible to the cancer treatment like radiation and. Hypoxiaactivated anticancer prodrug for bioimaging, tracking. The molecular oxygen o 2 level of normal tissues is 2%9% vv on average 40 mm hg po 2. Pdf hypoxiaactivated prodrugs and lack of clinical progress. Repurposing drugs in oncology redonitroglycerin as an anti. Hypoxiaactivated prodrugs could prevent drug resistance.
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