Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment

Cairns, Rob A.; Papandreou, Ioanna; Denko, Nicholas C.

doi:10.1158/1541-7786.mcr-06-0002

Cited by 319 publications

(256 citation statements)

References 105 publications

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“…Taxol can also act as an immunomodulator (29) to change the behavior of macrophages. Taxol has been shown to activate macrophages in a similar manner to lipopolysaccharide, increasing the expression of interleukin-12, tumor necrosis factor a, and nitric oxide, and some tumor cellderived cytokines can dysregulate the activation process (30). Thus, there are several mechanisms by which Taxol can affect SS1P action.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice

Zhang

Xiang

Hassan

et al. 2006

Clinical Cancer Research

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Purpose:To investigate the combined antitumor activity in mice of immunotoxin SS1P and Taxol.Methods: Immunodeficient mice were implanted with A431/K5 tumors expressing mesothelin. Established tumors were treated i.v. with immunotoxin SS1P alone, i.p. with Taxol alone, or with the two agents together. SS1P was radiolabeled with 111 In and used to study the effect of Taxol on its uptake by A431/K5 tumors. Results: Using doses at which either agent alone caused stabilization of tumor growth, the combination was synergistic causing long-lasting complete remissions in many animals. In contrast, synergy was not observed when the same cells were treated with these agents in vitro. Tumor uptake of 111In-SS1P was not affected by treatment withTaxol. Conclusion: The combination of Taxol and SS1P exerts a synergistic antitumor effect in animals but not in cell culture. This effect is not secondary to increased tumor uptake of the immunotoxin. Synergy could be due to improved immunotoxin distribution within the tumor or could involve factors released by other cell types in the tumors.

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Section: Discussionmentioning

confidence: 99%

Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice

Zhang

Xiang

Hassan

et al. 2006

Clinical Cancer Research

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“…Physiological conditions associated with solid tumors often lead to poor drug uptake, 44,45 which in the case of prodrug activation gene therapy may translate into inefficient prodrug activation. Presently, 4-OH-CPA production by P450 2B11-expressing 9L tumors was not saturated at a prodrug dose corresponding to a C max (CPA) of B200 mM, that is B3 times the observed K m of P450 2B11, suggesting inefficient penetration of CPA, despite the good vascularity of 9L tumors.…”

Section: Discussionmentioning

confidence: 99%

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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“…Hypoxia is a common feature in many solid tumors and the microenvironment is now recognized as a key factor linked to the biologically aggressive phenotypes and their resistance to chemotherapeutic agents and irradiation therapies (Teicher, 1994;Brown and Giaccia, 1998;Cairns et al, 2006). Extensive studies of molecular mechanisms have shown that transcription factor hypoxia-inducible factor-1a (HIF-1a) is a key regulator of hypoxic reaction; these studies have led to a better understanding of the mechanisms of HIF-1a activation and the subsequent alteration of gene expressions under hypoxic conditions (Harris, 2002;Denko et al, 2003;Semenza, 2003;Poellinger and Johnson, 2004).…”

Section: Introductionmentioning

confidence: 99%

Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2

et al. 2008

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Tumor hypoxia has been reported to cause a functional loss in DNA mismatch repair (MMR) system as a result of downregulation of MMR genes, although the precise molecular mechanisms remain unclear. In this study, we focused on the downregulation of a key MMR gene, MLH1, and demonstrated that hypoxia-inducible transcription repressors, differentiated embryo chondrocytes (DEC1 and 2), participated in its transcriptional regulation via their bindings to E-box-like motif(s) in MLH1 promoter region. In all cancer cell lines examined, hypoxia increased expression of DEC1 and 2, known as hypoxia-inducible genes, but decreased MLH1 expression in an exposure time-dependent manner at both the mRNA and protein levels. Co-transfection reporter assay revealed that DEC1 and, to greater extent, DEC2 as well as hypoxia-repressed MLH1 promoter activity. We further found that the action was remarkably inhibited by trichostatin A, and identified a possible DEC-response element in the MLH1 promoter. In vitro electrophoretic gel mobility shift and chromatin immunoprecipitation assays demonstrated that DEC1 or 2 directly bounds to the suggested element, and transient transfection assay revealed that overexpression of DEC2 repressed endogenous MLH1 expression in the cells. Hypoxia-induced DEC may impair MMR function through repression of MLH1 expression, possibly via the histone deacethylasemediated mechanism in cancer cells.

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Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment

Cited by 319 publications

References 105 publications

Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice

Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice

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

Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2

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