Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol™), a novel isoflav-3-ene, in patients with advanced cancer

Souza, Paul L. de; Links, Matthew; Pirabhahar, Saiyini; Kelly, Graham; Howes, L. G.

doi:10.1007/s00280-006-0189-6

Cited by 21 publications

(18 citation statements)

References 15 publications

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“…16,18 The pharmacokinetics, bioavailability, and safety of intravenous (IV) phenoxodiol have been established in previous phase I clinical trials. 19,20 The first use of IV phenoxodiol in ovarian cancer was conducted at our institution. Forty patients with recurrent ovarian, fallopian tube, or primary peritoneal cancers who had failed second-line therapy were treated with 1 of 4 dose levels (1, 3, 10, and 20 mg/kg) of IV phenoxodiol administered on 2 consecutive days per week.…”

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confidence: 99%

Phase II Evaluation of Phenoxodiol in Combination With Cisplatin or Paclitaxel in Women With Platinum/Taxane-Refractory/Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancers

Kelly¹,

Mor

Husband

et al. 2011

Int J Gynecol Cancer

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confidence: 99%

Phase II Evaluation of Phenoxodiol in Combination With Cisplatin or Paclitaxel in Women With Platinum/Taxane-Refractory/Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancers

Kelly¹,

Mor

Husband

et al. 2011

Int J Gynecol Cancer

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“…1,2 Phenoxodiol has been referred to as a pan-cancer drug, 3 causing apoptosis in cancer cell lines and murine cancer models via both intrinsic and extrinsic pathways. [4][5][6][7][8][9][10][11][12][13][14] Plasma membrane electron transport (PMET) has been shown to be a target of phenoxodiol in several studies with cancer cell lines.…”

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confidence: 99%

The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells

Herst¹,

Davis²,

Neeson³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundThe redox-active isoflavene anti-cancer drug, phenoxodiol, has previously been shown to inhibit plasma membrane electron transport and cell proliferation and promote apoptosis in a range of cancer cell lines and in anti-CD3/anti-CD28-activated murine splenocytes but not in non-transformed WI-38 cells and human umbilical vein endothelial cells. Design and MethodsWe determined the effects of phenoxodiol on plasma membrane electron transport, MTT responses and viability of activated and resting human T cells. In addition, we evaluated the effect of phenoxodiol on the viability of leukemic cell lines and primary myeloid and lymphoid leukemic blasts. ResultsWe demonstrated that phenoxodiol inhibited plasma membrane electron transport and cell proliferation (IC50 46 µM and 5.4 µM, respectively) and promoted apoptosis of rapidly proliferating human T cells but did not affect resting T cells. Phenoxodiol also induced apoptosis in T cells stimulated in HLA-mismatched allogeneic mixed lymphocyte reactions. Conversely, non-proliferating T cells in the mixed lymphocyte reaction remained viable and could be restimulated in a third party mixed lymphocyte reaction, in the absence of phenoxodiol. In addition, we demonstrated that leukemic blasts from patients with primary acute myeloid leukemia (n=22) and acute lymphocytic leukemia (n=8) were sensitive to phenoxodiol. The lymphocytic leukemic blasts were more sensitive than the myeloid leukemic blasts to 10 µM phenoxodiol exposure for 24h (viability of 23±4% and 64±5%, respectively, p=0.0002). ConclusionsThe ability of phenoxodiol to kill rapidly proliferating lymphocytes makes this drug a promising candidate for the treatment of pathologically-activated lymphocytes such as those in acute lymphoid leukemia, or diseases driven by T-cell proliferation such as autoimmune diseases and graft-versus-host disease.

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“…It may be capable of re-sensitising platinum-and taxane-resistant ovarian cancer cells in vitro (Kamsteeg et al, 2003;Sapi et al, 2004;Kluger et al, 2007) and appears to have antiangiogenic (Gamble et al, 2006) and anti-inflammatory properties (Widyarini et al, 2001). It has improved bioavailability when compared with genistein (Kelly and Husband, 2003) and low toxicity in clinical trials (Joshua et al, 2003;Choueiri et al, 2006a;de Souza et al, 2006).…”

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confidence: 99%

Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells

2009

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Phenoxodiol is a novel isoflav-3-ene, currently undergoing clinical trials, that has a broad in vitro activity against a number of human cancer cell lines. Phenoxodiol alone inhibited DU145 and PC3 in a dose-and time-dependent manner with IC 50 values of 8±1 and 38 ± 9 mM, respectively. The combination of phenoxodiol and cisplatin was synergistic in DU145, and additive in PC3, as assessed by the Chou -Talalay method. Carboplatin was also synergistic in combination with phenoxodiol in DU145 cells. The activity of the phenoxodiol and cisplatin combination was confirmed in vivo using a DU145 xenograft model in nude mice. Pharmacokinetic data from these mice suggest that the mechanism of synergy may occur through a pharmacodynamic mechanism. An intracellular cisplatin accumulation assay showed a 35% (Po0.05) increase in the uptake of cisplatin when it was combined in a ratio of 1 mM: 5 mM phenoxodiol, resulting in a 300% (Po0.05) increase in DNA adducts. Taken together, our results suggest that phenoxodiol has interesting properties that make combination therapy with cisplatin or carboplatin appealing.

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Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol™), a novel isoflav-3-ene, in patients with advanced cancer

Abstract: NV06 is well tolerated and can be given safely as an intravenous infusion over 1-2 h at a dose of at least 30 mg/kg.

Cited by 21 publications

References 15 publications

Phase II Evaluation of Phenoxodiol in Combination With Cisplatin or Paclitaxel in Women With Platinum/Taxane-Refractory/Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancers

Phase II Evaluation of Phenoxodiol in Combination With Cisplatin or Paclitaxel in Women With Platinum/Taxane-Refractory/Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancers

The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells

Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells

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