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      Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours

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          Abstract

          Background:

          Despite substantial improvements in childhood cancer survival, drug resistance remains problematic for several paediatric tumour types. The urgent need to access novel agents to treat drug-resistant disease should be expedited by pre-clinical evaluation of paediatric tumour models during the early stages of drug development in adult cancer patients.

          Methods/results:

          The novel cytotoxic RH1 (2,5-diaziridinyl-3-[hydroxymethyl]-6-methyl-1,4-benzoquinone) is activated by the obligate two-electron reductase DT-diaphorase (DTD, widely expressed in adult tumour cells) to a potent DNA interstrand cross-linker. In acute viability assays against neuroblastoma, osteosarcoma, and Ewing′s sarcoma cell lines RH1 IC 50 values ranged from 1-200 n M and drug potency correlated both with DTD levels and drug-induced apoptosis. However, synergy between RH1 and cisplatin or doxorubicin was only seen in low DTD expressing cell lines. In clonogenic assays RH1 IC 50 values ranged from 1.5–7.5 n M and drug potency did not correlate with DTD level. In A673 Ewing's sarcoma and 791T osteosarcoma tumour xenografts in mice RH1 induced apoptosis 24 h after a single bolus injection (0.4 mg/kg) and daily dosing for 5 days delayed tumour growth relative to control.

          Conclusion:

          The demonstration of RH1 efficacy against paediatric tumour cell lines, which was performed concurrently with the adult Phase 1 Trial, suggests that this agent may have clinical usefulness in childhood cancer.

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          Most cited references34

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          The unique physiology of solid tumors: opportunities (and problems) for cancer therapy.

          The physiology of solid tumors differs from that of normal tissues in a number of important aspects, the majority of which stem from differences between the two vasculatures. Compared with the regular, ordered vasculature of normal tissues, blood vessels in tumors are often highly abnormal, distended capillaries with leaky walls and sluggish flow. Tumor growth also requires continuous new vessel growth, or angiogenesis. These physiological differences can be problems for cancer treatment; for example, hypoxia in solid tumors leads to resistance to radiotherapy and to some anticancer drugs. However, these differences can also be exploited for selective cancer treatment. Here we review four such areas that are under active investigation: (a) hypoxia-selective cytotoxins take advantage of the unique low oxygen tension in the majority of human solid tumors. Tirapazamine, a drug in the final stages of clinical trials, is one of the more promising of these agents; (b) leaky tumor blood vessels can be exploited using liposomes that have been sterically stabilized to have a long intravascular half-life, allowing them to selectively accumulate in solid tumors; (c) the tumor microenvironment is a stimulus to angiogenenesis, and inhibition of angiogenesis can be a powerful anticancer therapy not susceptible to acquired drug resistance; and (d) we discuss attempts to use gene therapy activated either by the low oxygen environment or by necrotic regions of tumors.
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            A simple generalized equation for the analysis of multiple inhibitions of Michaelis-Menten kinetic systems.

            The summation of the effects of two or more reversible inhibitors of various types on the initial velocity of enzyme systems obeying Michaelis-Menten kinetics is described by the the general relation: (formula: see text) wherein v1,2,3...n is the velocity of reaction in the simultaneous presence of n inhibitors, vi is the velocity observed in the presence of each individual inhibitor, and v0 is the velocity in the absence of inhibition. The derivation is based on the assumption that each enzyme species can combine with no more than one of the inhibitors (i.e. the inhibitors are mutually exclusive). The above relationship holds irrespective of the number of inhibitors, the type of inhibition (competitive, noncompetitive, or uncompetitive), or the kinetic mechanism (sequential or ping-pong) of the enzyme reaction under consideration. Deviations from this equality define synergism or antagonism of inhibitors depending on whether the value of the left side of the above equation is greater or smaller than the right, respectively. Knowledge of the kinetic constants for substrates and inhibitors is not required. If two or more inhibitors act independently (i.e. are not mutually exclusive), their combined effects are necessarily synergistic. Under certain circumstances, described in the text, mutually nonexclusive inhibitors obey the fractional velocity product relationship: v1,2,3...n/v0 = (v1/v0) x (v2/v0) x (v3/v0)...(vn/v0).
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              Childhood cancer survival trends in Europe: a EUROCARE Working Group study.

              EUROCARE collected data from population-based cancer registries in 20 European countries. We used this data to compare childhood cancer survival time trends in Europe. Survival in 44,129 children diagnosed under the age of 15 years during 1983 to 1994 was analyzed. Sex- and age-adjusted 5-year survival trends for 10 common cancers and for all cancers combined were estimated for five regions (West Germany, the United Kingdom, Eastern Europe, Nordic countries, and West and South Europe) and Europe as a whole. Europe-wide trends for 14 rare cancers were estimated. For all cancers combined, 5-year survival increased from 65% for diagnoses in 1983 to 1985 to 75% in 1992 to 1994. Survival improved for all individual cancers except melanoma, osteosarcoma, and thyroid carcinoma; although for retinoblastoma, chondrosarcoma, and fibrosarcoma, improvements were not significant. The most marked improvements (50% to 66%) occurred in Eastern Europe. For common cancers, the greatest improvements were for leukemia and lymphomas, with risk of dying reducing significantly by 5% to 6% per year. Survival for CNS tumors improved significantly from 57% to 65%, with risk reducing by 3% per year. Risk reduced by 4% per year for neuroblastoma and 3% per year for Wilms' tumor and rhabdomyosarcoma. The survival gap between regions reduced over the period, particularly for acute nonlymphocytic leukemia, CNS tumors, and rhabdomyosarcoma. For rare Burkitt's lymphoma, hepatoblastoma, gonadal germ cell tumors, and nasopharyngeal carcinoma, risk reductions were at least 10% per year. These gratifying improvements in survival can often be plausibly related to advances in treatment. The prevalence of European adults with a history of childhood cancer will inevitably increase.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                02 June 2009
                30 June 2009
                07 July 2009
                : 101
                : 1
                : 55-63
                Affiliations
                [1 ]Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research Manchester, UK
                [2 ]Department of Paediatric Oncology, Royal Manchester Children's Hospital Manchester, UK
                [3 ]School of Cancer and Imaging Sciences, Faculty of Medical and Human Sciences, University of Manchester Manchester, UK
                Author notes
                [* ]Author for correspondence: guy.makin@ 123456manchester.ac.uk
                Article
                6605100
                10.1038/sj.bjc.6605100
                2713707
                19491903
                ecdefb35-6b9f-4cc8-9d37-3f2c16c1a9db
                Copyright 2009, Cancer Research UK
                History
                : 24 April 2009
                : 27 April 2009
                : 06 May 2009
                Categories
                Translational Therapeutics

                Oncology & Radiotherapy
                osteosarcoma,neuroblastoma,novel therapies,childhood cancer,ewing's sarcoma

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