FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1973801832> ?p ?o ?g. }

• W1973801832 endingPage "1834" @default.
• W1973801832 startingPage "1833" @default.
• W1973801832 abstract "EXPERIMENTAL CHEMOTHERAPISTS are aware of a rule in drug development which states that the chance of an anticancer agent being successful clinically, is not directly proportional to the elegance of the working hypothesis and the amount of time and effort put into its development. In fact, some cynics hold that the relationship is an inverse one. This rule reflects the major problem of experimental cancer chemotherapy, namely that the laboratory models used to investigate new chemicals do not accurately predict the behaviour of any type of human cancer. Thus, agents with excellent activity against transplanted rodent turnours, such as the nitrosoureas, have been quite disappointing in the clinic. It is no coincidence that some of the important advances in cancer chemotherapy, such as the discovery of the co-ordination complexes of platinum, have come not from planned drug development programmes based on screening or rational design, but initially from a chance observation made in the course of experiments unrelated to cancer chemotherapy. Nevertheless, at first sight, it is disappointing that Dirix and associates [l] report in this issue on the failure of E09, a bioreductive agent, to have activity in four independent phase II clinical trials [l] (pages 2019-2022). The aim of bioreductive agents is to act as prodrugs and by selective activation in hypoxic cells, remove a source of chemotherapy resistant cells that could otherwise regrow after treatment and lead to failure of therapy. The very nature of cancer means that most solid turnours, even when small, will be expected to contain necrotic zones on the borders of which will be chemotherapy resistant hypoxic cells. Thus, solid rodent tumours should be reasonably good models for the study of bioreductive agents. The existence of hypoxic cells in tumours and cell spheroids, and their resistance to conventional therapy has been amply proven, particularly by the efforts of the radiobiologists over the past 30 years, not only by physical and biochemical measurements but also by direct visualisation. Chapman and colleagues injected tumour bearing animals with a labelled nitroimidazole and showed covalent binding in autoradiographic sections exactly where they had been predicted, namely in cells close to central necrotic zones [2]. More recently, perfluorocarbons have been developed which contain up to twenty equivalent fluorine atoms and are highly sensitive reagents for NMR. Experiments on tumour bearing animals have shown that, under ideal conditions, hypoxic zones can be clearly visualised, and that these diminish in animals breathing carbogen [3]. There is a limited amount of ciinical evidence that abolition of the hypoxic fraction of tumours can improve responses to therapy. In some trials, a beneficial effect of hyperbaric oxygen and electron affinic radiation sensitisers on, for example, radiotherapy of head and neck cancers has been reported. An anecdotal report also claimed that tumours infected with anaerobic bacteria were particularly sensitive to nitroimidazole radiation sensitisers, suggesting that, besides sensitising as electron affinic agents, they were also acting as prodrugs, being converted, to covalent binding electrophilic reactants by the bacterial nitroreductases (as noted in the aforementioned Chapman studies). The concept of bioreductive prodrugs has been well validated and many different classes have been investigated, including a range of nitro compounds, N-oxides and chemicals acting by E09 type mechanisms [4]. In the paper by Dirix and associates, E09 given as a 5 minute i.v. infusion at a weekly dose of 12 mg/m2 to 22 patients with breast cancer, 26 with colon cancer, 24 with pancreatic cancer and 20 with gastric cancer gave no evidence of antitumour activity. In retrospect, it is surprising that so many phase II trials were carried on E09 as a single agent when theoretically one might not expect activity. It is possible, of course, that the inactivity was due to inappropriate pharmacokinetics, failure to reach hypoxic zones or even because the drug was not behaving as a prodrug as predicted. However, it is also a possibility that the drug is acting as a perfect bioreductive prodrug, in which case measurement of antitumour effect using conventional techniques might well give negative results. Many years ago, experiments were carried out on subcutaneously implanted tumours in rodents which could be accurately measured by calipers. A dose of cyclophosphamide which caused a small reduction in the volume of the tumour, nevertheless caused 99% tumour cell kill, followed by rapid regrowth, when measured by a clonogenic assay [5]. Since the hypoxic fraction of tumours, is unlikely to approach 90%, conventional measurements would be unable to detect any significant response, even if the hypoxic fraction was being totally removed by the action of E09. This is another example where a working hypothesis followed by research uncovers a new class of potentially useful agents which enter clinical trials that are not designed to validate the mechanism of action. Although no significant" @default.
• W1973801832 created "2016-06-24" @default.
• W1973801832 creator A5056997693 @default.
• W1973801832 date "1996-10-01" @default.
• W1973801832 modified "2023-09-25" @default.
• W1973801832 title "Bioreductive agents, hypoxie cells and therapy" @default.
• W1973801832 cites W1906753921 @default.
• W1973801832 cites W1973917355 @default.
• W1973801832 cites W1985330755 @default.
• W1973801832 cites W1987300521 @default.
• W1973801832 cites W1994216439 @default.
• W1973801832 cites W2131194912 @default.
• W1973801832 cites W2410410552 @default.
• W1973801832 cites W97656707 @default.
• W1973801832 doi "https://doi.org/10.1016/0959-8049(96)00305-x" @default.
• W1973801832 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/8943663" @default.
• W1973801832 hasPublicationYear "1996" @default.
• W1973801832 type Work @default.
• W1973801832 sameAs 1973801832 @default.
• W1973801832 citedByCount "12" @default.
• W1973801832 countsByYear W19738018322012 @default.
• W1973801832 countsByYear W19738018322016 @default.
• W1973801832 countsByYear W19738018322017 @default.
• W1973801832 countsByYear W19738018322018 @default.
• W1973801832 crossrefType "journal-article" @default.
• W1973801832 hasAuthorship W1973801832A5056997693 @default.
• W1973801832 hasConcept C177713679 @default.
• W1973801832 hasConcept C178790620 @default.
• W1973801832 hasConcept C185592680 @default.
• W1973801832 hasConcept C540031477 @default.
• W1973801832 hasConcept C71924100 @default.
• W1973801832 hasConcept C7836513 @default.
• W1973801832 hasConceptScore W1973801832C177713679 @default.
• W1973801832 hasConceptScore W1973801832C178790620 @default.
• W1973801832 hasConceptScore W1973801832C185592680 @default.
• W1973801832 hasConceptScore W1973801832C540031477 @default.
• W1973801832 hasConceptScore W1973801832C71924100 @default.
• W1973801832 hasConceptScore W1973801832C7836513 @default.
• W1973801832 hasIssue "11" @default.
• W1973801832 hasLocation W19738018321 @default.
• W1973801832 hasLocation W19738018322 @default.
• W1973801832 hasOpenAccess W1973801832 @default.
• W1973801832 hasPrimaryLocation W19738018321 @default.
• W1973801832 hasRelatedWork W1995515455 @default.
• W1973801832 hasRelatedWork W2039318446 @default.
• W1973801832 hasRelatedWork W2080531066 @default.
• W1973801832 hasRelatedWork W2144792843 @default.
• W1973801832 hasRelatedWork W2748952813 @default.
• W1973801832 hasRelatedWork W2899084033 @default.
• W1973801832 hasRelatedWork W3031052312 @default.
• W1973801832 hasRelatedWork W3032375762 @default.
• W1973801832 hasRelatedWork W3108674512 @default.
• W1973801832 hasRelatedWork W4252371801 @default.
• W1973801832 hasVolume "32" @default.
• W1973801832 isParatext "false" @default.
• W1973801832 isRetracted "false" @default.
• W1973801832 magId "1973801832" @default.
• W1973801832 workType "article" @default.