Phase I Study of MetXia-P450 Gene Therapy and Oral Cyclophosphamide for Patients with Advanced Breast Cancer or Melanoma

Braybrooke, Jeremy; Slade, Andrew; Deplanque, Gaël; Harrop, Richard; Madhusudan, Srinivasan; Förster, Martin; Gibson, Rachel J.; Makris, Andreas; Talbot, Denis; Steiner, Jan; White, Linda R.; Kan, On; Naylor, Stuart; Carroll, Miles W.; Kingsman, S.; Harris, Adrian L.

doi:10.1158/1078-0432.ccr-04-0155

Cited by 88 publications

(66 citation statements)

References 17 publications

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“…Our findings demonstrate that despite an increase in chemosensitivity, tumor cell expression of the high K m CPA 4-hydroxylase enzymes P450 2B6 and P450 2B1, used in recent clinical trials, 20,21 does not lead to a measurable increase in i.t. 4-OH-CPA levels.…”

Section: Introductionmentioning

confidence: 61%

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

Chen

Jounaïdi

et al. 2007

Cancer Gene Ther

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The therapeutic utility of cytochrome P450-based enzyme prodrug therapy is well established by preclinical studies and in initial clinical trials. The underlying premise of this gene therapy is that intratumoral P450 expression leads to in situ activation of anticancer P450 prodrugs, such as cyclophosphamide (CPA), with intratumoral accumulation of its activated 4-OH metabolite. In mice bearing 9L gliosarcomas expressing the CPA 4-hydroxylase P450 2B6, enhanced tumor apoptosis was observed 48 h after CPA treatment; however, intratumoral 4-OH-CPA levels were indistinguishable from those of P450-deficient tumors, indicating that the bulk of activated CPA is derived from hepatic metabolism. In contrast, in 9L tumors expressing P450 2B11, a low K m CPA 4-hydroxylase, intratumoral 4-OH-CPA levels were higher than in blood, liver and P450-deficient tumors. Intratumoral 4-OH-CPA increased dose-dependently, without saturation at 140 mg kg À1 CPA, suggesting restricted tumor cell permeation of the parent drug. To circumvent this problem, CPA was administered by direct intratumoral injection, which increased the maximum concentration and area under the curve of drug concentration Â time (AUC) of intratumoral 4-OH-CPA by 1.8-and 2.7-fold, respectively. An overall 3.9-fold increase in intratumoral 4-OH-CPA AUC, and in antitumor activity, was obtained when CPA release to systemic circulation was delayed using the slow-release polymer poloxamer 407 as vehicle for intratumoral CPA delivery. These findings highlight the advantage of gene therapy strategies that combine low K m P450 prodrug activation enzymes with slow, localized release of P450 prodrug substrates.

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Section: Introductionmentioning

confidence: 61%

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

Chen

Jounaïdi

et al. 2007

Cancer Gene Ther

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“…P450 gene transfer can be achieved both in cell culture and in human xenograft models by using tumor cell replication-conditional herpesvirus (24,25) or adenovirus vectors (26) to effect efficient, tumor-selective P450 gene delivery. Recent phase I/II clinical trials support the clinical development of P450 GDEPT based on studies using cellular vectors to deliver P450 2B1 to advanced pancreatic cancer patients treated with ifosfamide (27,28) and retroviral vectors to deliver P450 2B6 to advanced breast cancer and melanoma patients given oral cyclophosphamide (29).…”

Section: Introductionmentioning

confidence: 99%

Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11

Jounaïdi

Chen

Veal

et al. 2006

Molecular Cancer Therapeutics

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Gene therapy using the prodrug-activating enzyme P450 2B6 has shown substantial promise in preclinical and initial clinical studies with the P450 prodrugs cyclophosphamide and ifosfamide. We sought to optimize this therapy using the canine P450 enzyme 2B11, which activates cyclophosphamide and ifosfamide with K m of 80 to 160 Mmol/L, f10-to 20-fold lower than the K m of P450 2B6. Retrovirus encoding a P450 2B11-internal ribosome entry signal-P450 reductase expression cassette induced marked cyclophosphamide and ifosfamide cytotoxicity toward 9L gliosarcoma cells and exhibited an impressive bystander killing effect at micromolar prodrug concentrations, where P450 2B6 displayed low activity. Adeno-2B11, a replication-defective, E1/E3 region-deleted adenovirus engineered to coexpress P450 2B11 and P450 reductase, dramatically increased tumor cell-catalyzed cyclophosphamide 4-hydroxylation and cytotoxicity compared with Adeno-2B6 and effected strong bystander killing at low (20 Mmol/L) cyclophosphamide concentrations. Further increases in cyclophosphamide cytotoxicity were obtained in several human cancer cell lines, including a 4-hydroperoxycyclophosphamide-resistant MCF-7 breast cancer cell line, when Adeno-2B11 was combined with Onyx-017, an E1b-55-kDa gene-deleted, tumor cellreplicating adenovirus that coamplifies and facilitates tumor cell spread of Adeno-2B11. To evaluate the therapeutic effect of P450 2B11 expression in vivo, 9L gliosarcoma cells transduced with P450-expressing retrovirus were grown as solid s.c. tumors in immunodeficient mice. Cyclophosphamide treatment on a metronomic, 6-day repeating schedule led to full regression of 9L/2B11 tumors but not P450-deficient control tumors, resulting in a tumor-free period lasting up to f100 days. 9L/2B6 tumors regressed more slowly and exhibited a tumor-free period of only 21 to 39 days. Thus, P450 genedirected enzyme prodrug therapy can be greatly improved by using the low K m P450 enzyme 2B11, which catalyzes intratumoral activation of cyclophosphamide and ifosfamide at pharmacologically relevant drug concentrations.

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“…However, results of clinical trials have shown that, among other challenges, poor in vivo gene transfer efficiency poses a major obstacle for those approaches that rely on in vivo gene transfer into tumor cells. [1][2][3][4][5][6][7][8] This applies to 'suicide gene' therapy, oncogene antagonism, antiangiogenesis gene therapy and some forms of immunotherapy. Thus, intense efforts are being directed at modifying vectors and delivery systems in order to improve gene transfer.…”

Section: Introductionmentioning

confidence: 99%

Enriching suicide gene bearing tumor cells for an increased bystander effect

et al. 2006

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The success of cancer gene therapies requiring in vivo gene transfer is severely hampered by the low efficacy of gene transfer, which has been difficult to improve. We therefore established a novel strategy to increase the share of transduced cells post gene transfer. We hypothesized that in vivo selection of tumor cells transduced with a suicide gene effectively enriches these cells within a tumor, thus allowing for an increased bystander effect after the prodrug is given, leading to enhanced eradication of tumor cells. We reasoned that in vivo enrichment should be achieved by exploiting the metabolism of the suicide gene product. For this 'enrichment-eradication' strategy we chose a fusion gene of cytosine deaminase and uracil phosphoribosyl transferase. Positive selection (enrichment) was to be achieved by concurrently giving N-(phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine de novo synthesis, which leads to pyrimidine depletion-mediated death of non-transduced cells, and cytosine, to rescue fusion gene expressing cells via the pyrimidine salvage pathway. Negative selection (eradication) was to be induced by giving the prodrug 5-fluorocytosine. Indeed, murine NXS2 neuroblastoma cells transduced with the fusion gene were effectively enriched in vitro, leading to a near-complete bystander effect. In vivo enrichment-eradication of NXS2 cells led to decreased tumor growth. This proof-of-principle study shows that enrichment-eradication may compensate the effects of low in vivo gene transfer efficacy, a major obstacle in cancer gene therapy.

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Phase I Study of MetXia-P450 Gene Therapy and Oral Cyclophosphamide for Patients with Advanced Breast Cancer or Melanoma

Cited by 88 publications

References 17 publications

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11

Enriching suicide gene bearing tumor cells for an increased bystander effect

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