Therapeutic Significance of Microenvironmental Factors

Chaplin, David J.; Horsman, Michael R.; Trotter, M.J.; Siemann, Dietmar W.

doi:10.1007/978-3-642-58813-6_13

Cited by 9 publications

(4 citation statements)

References 59 publications

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“…If the chemotherapeutic drug itself is a weak acid or base, the degree of dissociation depends on the extracellular pH which may in turn affect the cellular uptake of the drug. In the case of a weak base, the intracellular concentration will be much smaller in an acidic environment when compared with a basic one 49. Because daunorubicin has a pK a of 8.4650 this mechanism of pH‐dependent uptake might play an additional role for the reduced cytotoxicity observed in the present study.…”

Section: Discussionmentioning

confidence: 61%

Acidosis induces multi‐drug resistance in rat prostate cancer cells (AT1) in vitro and in vivo by increasing the activity of the p‐glycoprotein via activation of p38

Sauvant

Nowak

Wirth

et al. 2008

Intl Journal of Cancer

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Because solid growing tumors often show hypoxia and pronounced extracellular acidosis, the aim of this study was to analyze the impact of an acidotic environment on the activity of the p-glycoprotein (pGP) and on the cellular content and cytotoxicity of the chemotherapeutic drug daunorubicin in the AT1 R-3327 Dunning prostate carcinoma cell line cultured in vitro and in vivo. In vitro, extracellular acidosis (pH 6.6) activated p38 and ERK1/2 and thereby induced daunorubicin resistance via a pronounced activation of pGP. De-novo protein synthesis was not necessary and analysis of transport kinetics indicated a fast and persistent pGP activation at pH 6.6 (when compared with 7.4). Intracellular acidification also induced daunorubicin resistance via activation of pGP, which was mediated by activation of p38 alone. In vivo, tumors were implanted subcutaneously, and the tumor pH was artificially lowered by forcing anaerobic metabolism. In vivo, the reduced extracellular pH of 6.6 was also able to induce daunorubicin resistance, which was abolished by inhibition of p38. These results suggest that pGP activity is dependent on extracellular pH in vitro and in vivo. Moreover, there is strong indication that this effect is mediated via activation of p38 in vivo. Activation of ERK is also suitable to induce pGP activity. Therefore, inhibition of p38 (and ERK) may be used to prevent acidosis induced increase in pGP activity and thereby attenuate multidrug resistance. In addition, supportive treatments reducing tumor acidosis may improve the cytotoxic effect of chemotherapeutic drugs.

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Section: Discussionmentioning

confidence: 61%

Acidosis induces multi‐drug resistance in rat prostate cancer cells (AT1) in vitro and in vivo by increasing the activity of the p‐glycoprotein via activation of p38

Sauvant

Nowak

Wirth

et al. 2008

Intl Journal of Cancer

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“…Also, the extracellular pH is lower in hypoxic than in well-oxygenated areas, while the intracellular pH is kept constant (Griffiths, 1991). This leads to the uptake and activity of weak acids such as chlorambucil to be increased, while that of weak bases like vinblastine to be decreased (Chaplin et al, 1998). Finally, hypoxia can induce the production of stress proteins responsible for resistance to doxorubicin, etoposide and methotrexate (Shen et al, 1987;Hughes et al, 1989;Sanna and Rofstad, 1994).…”

Section: Chemoresistancementioning

confidence: 99%

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Greco

Marples

Joiner

et al. 2003

Journal Cellular Physiology

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Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), or to exploit this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy.

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“…Abnormalities in tumor microvasculature structure and function contribute to the pathophysiologic microenvironment of tumors, which is characterized by inadequate oxygen delivery for the metabolic demands of the tissue. [1][2][3][4][5][6] It is well established that hypoxia can influence tumor biology and physiology, gene expression, metastatic potential, treatment efficacy, and patient survival. In addition to the detrimental effect on radiosensitivity, 7 hypoxia can have a direct and indirect negative impact on chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors

et al. 2008

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Abnormal microvasculature contributes to the pathophysiologic microenvironment of tumors. Understanding microvascular tumor oxygen transport is necessary to comprehend the factors that influence tumor biology, physiology, and therapy. Previously, we described an in vivo spectral imaging microscopy system for measurements of microvessel hemoglobin saturation (HbSat). We measure temporal fluctuations and spatial gradients in tumor microvessel oxygenation and identify instances of anastomoses between vessels with significantly different oxygenations. Slow periodic fluctuations in HbSat <0.2 cycles per minute were observed. These measurements are consistent with microelectrode measurements of fluctuating tumor oxygenation. Gradients in HbSat along individual tumor microvessels were measured that were larger in magnitude than normal tissue microvessels. Images were captured of anastomoses of tumor microvessels with diameters 20%). Shunting of inspired oxygen, presumably due to arteriovenous anastomoses, from tumor feeding arterioles to adjacent venules was imaged. This effect was confined to a region around the tumor and was not observed in nearby normal microvessels. Imaging measurements of tumor microvessel oxygen transport may offer insight to current questions regarding oxygen-related tumor biology and treatment responses, and spectral imaging may be a useful research tool in this regard.

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Therapeutic Significance of Microenvironmental Factors

Cited by 9 publications

References 59 publications

Acidosis induces multi‐drug resistance in rat prostate cancer cells (AT1) in vitro and in vivo by increasing the activity of the p‐glycoprotein via activation of p38

Acidosis induces multi‐drug resistance in rat prostate cancer cells (AT1) in vitro and in vivo by increasing the activity of the p‐glycoprotein via activation of p38

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors

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