Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

Newell, David R.; Searle, Karlee; Westwood, Nigel; Burtles, S S

doi:10.1038/sj.bjc.6601106

Cited by 13 publications

(9 citation statements)

References 110 publications

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“…The photographs are representative of three replicate seedlings assessed for each treatment, and the experiment was done twice with nearly identical results. (15,23,48), however, rhizoxin was never taken into phase III clinical trials (35), shifting the focus of the biological significance toward its antifungal properties (17). Strains of Pseudomonas spp.…”

Section: Compoundmentioning

confidence: 99%

Isolation and Identification of Rhizoxin Analogs from Pseudomonas fluorescens Pf-5 by Using a Genomic Mining Strategy

Loper

Henkels

Shaffer

et al. 2008

Appl Environ Microbiol

113

101

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The products synthesized from a hybrid polyketide synthase/nonribosomal peptide synthetase gene cluster in the genome of Pseudomonas fluorescens Pf-5 were identified using a genomics-guided strategy involving insertional mutagenesis and subsequent metabolite profiling. Five analogs of rhizoxin, a 16-member macrolide with antifungal, phytotoxic, and antitumor activities, were produced by Pf-5, but not by a mutant with an insertion in the gene cluster. The five rhizoxin analogs, one of which had not been described previously, were differentially toxic to two agriculturally important plant pathogens, Botrytis cinerea and Phytophthora ramorum. The rhizoxin analogs also caused swelling of rice roots, a symptom characteristic of rhizoxin itself, but were less toxic to pea and cucumber roots. Of the rhizoxin analogs produced by Pf-5, the predominant compound, WF-1360 F, and the newly described compound 22Z-WF-1360 F were most toxic against the two plant pathogens and three plant species. These rhizoxin analogs were tested against a panel of human cancer lines, and they exhibited potent but nonselective cytotoxicity. This study highlights the value of the genomic sequence of the soil bacterium P. fluorescens Pf-5 in providing leads for the discovery of novel metabolites with significant biological properties.Secondary-metabolite production is a striking characteristic of Pseudomonas spp. (5, 28), and the current availability of genomic sequence data for several Pseudomonas spp. further highlights the capacity for secondary-metabolite production in this group of bacteria. For example, at least 6% of the genome of Pseudomonas fluorescens Pf-5, a rhizosphere bacterium that suppresses plant diseases, is devoted to secondary metabolism, with gene clusters for the biosynthesis of two siderophores, hydrogen cyanide, and several antibiotics (pyrrolnitrin, 2,4-diacetylphloroglucinol, and pyoluteorin) distributed throughout the genome (30). In addition to the secondary metabolites known to be produced by Pf-5 prior to genomic sequencing, three orphan gene clusters were identified in the genome of this bacterium (41). These three orphan genetic loci contain sequences that are characteristic of polyketide synthases (PKS) or nonribosomal peptide synthetases (NRPS) (51). One of the orphan metabolites has since been identified as orfamide A, the founder of a new group of bioactive cyclic lipopeptides that lyses zoospores of an oomycete plant pathogen and functions in the swarming motility of Pf-5 (11). In our continuing effort to identify the products of orphan pathways from the P. fluorescens Pf-5 genome, we describe here the products of a cluster containing genes with characteristic sequences of both PKS and NRPS. Using a screening strategy comparing Pf-5 to a derivative with a mutation in this cluster (12), we isolated and identified several metabolites structurally related to rhizoxin (Fig.

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Section: Compoundmentioning

confidence: 99%

Isolation and Identification of Rhizoxin Analogs from Pseudomonas fluorescens Pf-5 by Using a Genomic Mining Strategy

Loper

Henkels

Shaffer

et al. 2008

Appl Environ Microbiol

113

101

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“…Banoxantrone (AQ4N) is a hypoxia-activated prodrug currently in phase I/II clinical trials (19). AQ4N undergoes two sequential 2e -reductions, via the mono N-oxide AQM, to give AQ4, a potent topoisomerase II inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N)

Mehibel

Singh

Chinje

et al. 2009

Molecular Cancer Therapeutics

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Tumor-associated macrophages (TAMs) are found in many solid tumors and have often been shown to accumulate in the hypoxic regions surrounding areas of necrosis. TAMs are the major site of expression of nitric oxide synthase (NOS), a heme-containing homodimeric enzyme consisting of oxygenase and reductase domains. The latter has a high degree of sequence homology to cytochrome P450 reductase and a functional consequence of this is the ability of NOS, under hypoxic conditions, to activate the bioreductive drugs tirapazamine and RSU1069. Banoxantrone (AQ4N) is a bioreductive prodrug activated in hypoxia by an oxygen-dependent two-electron reductive process to yield the topoisomerase II inhibitor AQ4. A feature of this process is that the final product could potentially show bystander cell killing. Thus, in this study, we investigated the ability of inducible NOS (iNOS)-expressing TAMs to activate AQ4N and elicit toxicity in cocultured human tumor cells. Murine macrophages were induced to overexpress iNOS by treatment with a combination of cytokines, mixed with HT1080 and HCT116 human tumor cells, and the toxicity of AQ4N was determined under aerobic or hypoxic conditions. The aerobic toxicity of AQ4N toward tumor cells was not affected through coculturing with macrophages. However, under hypoxic conditions, the induction of iNOS activity in the macrophages was associated with an increase in AQ4N metabolism and a substantial increase in tumor cell toxicity, which was dependent on the proportion of macrophages in the culture. This study is the first demonstration of TAM-mediated prodrug activation to result in bystander killing of human tumor cells.

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“…This increased understanding has been accompanied by new technologies that speed up the search for, and development of, new therapeutics (Workman and Kaye, 2002). Given the greater specificity of new agents against target processes, together with an expected growth in the number of such agents being proposed for clinical trial, the New Agents Committee (NAC) of Cancer Research UK, which approves and supports clinical trials of promising cancer therapeutics, is placing considerable emphasis on incorporating end points that provide evidence that the desired activity has been achieved into new trials (Newell et al, 2003). To assist in this, the Pharmacodynamic/Pharmacokinetic Technologies Advisory Committee (PTAC) reviews submissions to the NAC for new therapeutics being considered for further development or clinical trial, to identify and advise on the incorporation of pharmacodynamic and pharmacokinetic assessment into earlystage clinical trials (http://science.cancerresearchuk.org/tcr/drugdevelopment/newagentscomm/ptac).…”

mentioning

confidence: 99%

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

et al. 2005

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Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.

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Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

Cited by 13 publications

References 110 publications

Isolation and Identification of Rhizoxin Analogs from Pseudomonas fluorescens Pf-5 by Using a Genomic Mining Strategy

Isolation and Identification of Rhizoxin Analogs from Pseudomonas fluorescens Pf-5 by Using a Genomic Mining Strategy

Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N)

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

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