Tumour hypoxia: challenges for cancer chemotherapy

Wilson, William R.

doi:10.1007/978-94-009-0385-2_4

Cited by 23 publications

(64 citation statements)

References 180 publications

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“…Hypoxia impedes drugs from reaching the cells from blood vessels, slows proliferation, and promotes gene expression changes that enable cellular rescue from severe damage (101,102). To address the clinical problem of tumor resistance associated with hypoxia, the focus for several decades has been to improve O 2 levels in the tumor environment or to use O 2 -independent irradiation (neutrons), altered fractionation, or radiosensitizers.…”

Section: Imaging Fundamental Properties Of Neoplasiamentioning

confidence: 99%

The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development

Kelloff

Krohn

Larson

et al. 2005

Clinical Cancer Research

203

142

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As addressed by the recent Food and Drug Administration Critical Path Initiative, tools are urgently needed to increase the speed, efficiency, and cost-effectiveness of drug development for cancer and other diseases. Molecular imaging probes developed based on recent scientific advances have great potential as oncologic drug development tools. Basic science studies using molecular imaging probes can help to identify and characterize disease-specific targets for oncologic drug therapy. Imaging end points, based on these disease-specific biomarkers, hold great promise to better define, stratify, and enrich study groups and to provide direct biological measures of response. Imaging-based biomarkers also have promise for speeding drug evaluation by supplementing or replacing preclinical and clinical pharmacokinetic and pharmacodynamic evaluations, including target interaction and modulation. Such analyses may be particularly valuable in early comparative studies among candidates designed to interact with the same molecular target. Finally, as response biomarkers, imaging end points that characterize tumor vitality, growth, or apoptosis can also serve as early surrogates of therapy success. This article outlines the scientific basis of oncology imaging probes and presents examples of probes that could facilitate progress. The current regulatory opportunities for new and existing probe development and testing are also reviewed, with a focus on recent Food and Drug Administration guidance to facilitate early clinical development of promising probes. Value of Imaging-Based Biomarkers in Drug DevelopmentIn the last 10 years, novel treatments have been developed that prolong survival, induce remission, and provide better quality of life for cancer patients. Among the successes are the molecularly targeted cancer treatment drugs, notably the anti-HER-2/neu antibody trastuzumab for ErbB2-expressing breast cancers (1) and the kinase inhibitor imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors (2). In addition, molecularly targeted drugs have shown efficacy in lung cancer [e.g., the epidermal growth factor receptor (EGFR) inhibitor erlotinib; ref. 3], multiple myeloma (e.g., the proteasome inhibitor bortezomib; ref. 4), advanced colorectal cancer (e.g., the EGFR antibody cetuximab; refs. 5, 6), and other breast cancer settings (e.g., the aromatase inhibitor letrozole for hormone receptor -unknown or hormone receptor -positive locally advanced or metastatic breast cancer in postmenopausal women; ref. 7). Despite their efficacy in certain settings, molecularly targeted drugs are resource-intensive to develop, with the considerable expenditures, protracted time, and numerous patients required during development resulting in high costs of the approved therapy (8). Moreover, molecular targets have been identified and characterized in relatively few oncology patients; improved phenotypic characterization of the underlying molecular lesions would expand the overall effect of targeted agents in onc...

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Section: Imaging Fundamental Properties Of Neoplasiamentioning

confidence: 99%

The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development

Kelloff

Krohn

Larson

et al. 2005

Clinical Cancer Research

203

142

View full text Add to dashboard Cite

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“…Most such compounds are activated by metabolic reduction and are therefore commonly referred to as bioreductive drugs. A wide variety of compounds from different structural classes are currently under preclinical or clinical investigation as bioreductive drugs (Wilson 1992;Adams & Stratford 1994). Five different redox centres have been used as reductive 'triggers' in these compounds; an example of each is illustrated in Fig.…”

Section: Bioreductive D R U G Smentioning

confidence: 99%

“…1988;Overgaard 1992;Hockel et al 1993). Less is known about the contribution of hypoxic cells to failure of chemotherapy, although there are compelling reasons to expect such cells to be resistant to some types of cytotoxic drugs (Wilson 1992).…”

Section: Introductionmentioning

confidence: 99%

Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: HYPOXIA‐ACTIVATED PRODRUGS AS ANTITUMOUR AGENTS: STRATEGIES FOR MAXIMIZING TUMOUR CELL KILLING

Wilson

Pruijn

1995

Clin Exp Pharma Physio

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1. Hypoxia arises in solid tumour because of inefficient blood supply. While hypoxic cells are resistant to radiotherapy and probably to many chemotherapeutic drugs they can, in principle, be turned to advantage through the development of hypoxia-activated cytotoxic drugs (bioreductive drugs). 2. Three general approaches to exploiting tumour hypoxia are discussed. The first relies on fluctuating blood flow in tumours and the consequent cycling of cells through the hypoxic compartment. The second incorporates a prodrug approach in which drug activation gives rise to cytotoxic metabolites which diffuse out of hypoxic zones. The third utilizes selective inhibitors of tumour blood flow to induce additional hypoxia and thus enhance bioreductive drug activation. 3. The latter two approaches are illustrated by recent studies with the dinitrobenzamide nitrogen mustard class of bioreductive drugs and their combination with the tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid.

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“…Bioreductive agents are prodrugs that can undergo enzymatic reduction‐mediated activation only under low oxygen tension [1,2], such as the hypoxic environment known to exist primarily in solid tumours [3]. Tumour‐associated hypoxia has a profound influence on the outcome of cancer radiotherapy and chemotherapy and is a strong prognostic factor of disease progression, metastasis and survival [4–6]. Therefore, bioreductive agents have been developed over the years in an effort to overcome the obstacle of hypoxia‐mediated resistance of tumours to common modality treatment.…”

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confidence: 99%

Hypoxia-Dependent Retinal Toxicity of NLCQ-1 (NSC 709257) in BALB/c Mice. Comparison with Tirapazamine

Papadopoulou

Bloomer

2011

Basic &Amp; Clinical Pharmacology &Amp; Toxicology

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Bioreductive drugs can cause retinal toxicity, mediated by extensive apoptosis in the outer retina of rodents and monkeys. In the present study, we have investigated whether or not the novel and promising hypoxia-selective cytotoxin 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257) can cause hypoxia-dependent retinal toxicity in BALB ⁄ c mice alone or in combination with cyclophosphamide (CPM), one of the anti-cancer agents that acts synergistically with NLCQ-1 against mouse tumours and human xenografts. The bioreductive agent tirapazamine (TPZ) was included for comparison purposes. Retinal damage was quantified by morphometric analysis of histological sections following IP treatment of female BALB ⁄ c mice. No retinal toxicity was observed with 10 or 22 mg ⁄ kg of NLCQ-1 or 23 mg ⁄ kg TPZ alone, whereas statistically significant retinal toxicity was observed with the higher TPZ dose of 52 mg ⁄ kg (p < 0.001). Thus, a normalized photoreceptor layer thickness (NPT) value of 0.50 € 0.04, 0.48 € 0.03 and 0.33 € 0.06 was determined for untreated, NLCQ-1 and TPZ-treated mice at the highest dose, respectively. Marginal retinal toxicity was observed with the lower dose of TPZ in combination with CPM.

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Tumour hypoxia: challenges for cancer chemotherapy

Cited by 23 publications

References 180 publications

The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development

The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development

Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: HYPOXIA‐ACTIVATED PRODRUGS AS ANTITUMOUR AGENTS: STRATEGIES FOR MAXIMIZING TUMOUR CELL KILLING

Hypoxia-Dependent Retinal Toxicity of NLCQ-1 (NSC 709257) in BALB/c Mice. Comparison with Tirapazamine

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