A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer

Rustin, G. J. S.; Shreeves, Gavin; Nathan, Paul; Gaya, Andrew; Ganesan, Trivadi S.; Wang, D; Boxall, J; Poupard, L.; Chaplin, David J.; Stratford, Michael R.L.; Balkissoon, Jai; Zweifel, Martin

doi:10.1038/sj.bjc.6605650

Cited by 125 publications

(93 citation statements)

References 21 publications

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“…2a was found to have potent anticancer activity against a number of human cancer cell lines including multi-drug resistant cancer cell lines and binds to the colchicine-binding site of tubulin 10 . A water-soluble prodrug, combretastatin A-4-phosphate (2b, figure 1) is now in clinical trials for thyroid cancer [11][12][13] and in patients with advanced cancer 14 . 2b induces vascular shutdown within tumours at doses less than one-tenth of the maximum tolerated dose and without detectable morbidity, assuming a MTD of 1000mg/kg 7 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

et al. 2010

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Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

et al. 2010

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“…For these reasons, combination strategies with cytotoxic agents or radiotherapy aiming to interfere with the tumor recovery that ensues after VDA therapy have been actively evaluated both preclinically (1,(8)(9)(10) and clinically (4,(11)(12)(13). The future success of VDAs will most likely rely on advances in deciphering the mechanisms underlying VDAinduced tumor resistance and determining optimal agents and schedules that will improve the antitumor activity of these drugs.…”

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confidence: 99%

Reversing Resistance to Vascular-Disrupting Agents by Blocking Late Mobilization of Circulating Endothelial Progenitor Cells

et al. 2012

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The prevailing concept is that immediate mobilization of bone marrow-derived circulating endothelial progenitor cells (CEP) is a key mechanism mediating tumor resistance to vascular-disrupting agents (VDA). Here, we show that administration of VDA to tumor-bearing mice induces 2 distinct peaks in CEPs: an early, unspecific CEP efflux followed by a late yet more dramatic tumor-specific CEP burst that infiltrates tumors and is recruited to vessels. Combination with antiangiogenic drugs could not disrupt the early peak but completely abrogated the late VDA-induced CEP burst, blunted bone marrow-derived cell recruitment to tumors, and resulted in striking antitumor efficacy, indicating that the late CEP burst might be crucial to tumor recovery after VDA therapy. CEP and circulating endothelial cell kinetics in VDA-treated patients with cancer were remarkably consistent with our preclinical data. These findings expand the current understanding of vasculogenic "rebounds" that may be targeted to improve VDA-based strategies. SIGNIFICANCE: Our findings suggest that resistance to VDA therapy may be strongly mediated by late, rather than early, tumor-specific recruitment of CEPs, the suppression of which resulted in increased VDA-mediated antitumor efficacy. VDA-based therapy might thus be significantly enhanced by combination strategies targeting late CEP mobilization. Cancer Discov; 2(5); 434-49.

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“…The anti-vascular effects of Z-combretastatins led to phase I-III clinical trials in which a sodium diphosphate derivative of Z-combretastatin A4 (Z-CA4) was tested as potential anti-angiogenic anticancer agent. Unfortunately the combretastatin phosphate salt displayed severe side effects such as cardiovascular toxicity that prevented the compound from making its way to the clinic [118,119]. The E-combretastatin pro-drug uptake and distribution in live cells can be monitored by multiphoton FLIM imaging at 625 nm [120].…”

Section: Alternative Strategy For Two-photon Phototherapy (2p-pdt) Wimentioning

confidence: 99%

New Approaches to Photodynamic Therapy from Types I, II and III to Type IV Using One or More Photons

Scherer

Bisby²,

Botchway³

et al. 2017

ACAMC

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Photodynamic therapy (PDT) is an alternative cancer treatment to conventional surgery, radiotherapy and chemotherapy. It is based on activating a drug with light that triggers the generation of cytotoxic species that promote tumour cell killing. At present, PDT is mainly used in the treatment of wet age-related macular degeneration, for precancerous conditions of the skin (e.g. actinic keratosis) and in the palliative care of advanced cancers, for instance of the bladder or the oesophagus. Due to a lack of phase III clinical trials and limitations of light penetration to deeper lying tumours (in excess of 1 cm), PDT is still not used as a first line cancer treatment, which is surprising given the first clinical trials by Dougherty's group dating back to the 1970's. However research continues to demonstrate the potential benefits of PDT and the need to stimulate funding and uptake of clinical studies using next generation photosensitizers offering advanced targeted delivery, improved photodynamic dose combined with modern light delivery technologies. This review surveys the available PDT treatments and emerging novel developments in the field with a particular focus on two-photon techniques that are anticipated to improve the effectiveness of PDT in tissues at depth and on next generation drugs that work without the need of the presence of oxygen for photosensitization making them effective where hypoxia has taken hold.

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A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer

Cited by 125 publications

References 21 publications

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

Reversing Resistance to Vascular-Disrupting Agents by Blocking Late Mobilization of Circulating Endothelial Progenitor Cells

New Approaches to Photodynamic Therapy from Types I, II and III to Type IV Using One or More Photons

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