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Hyperbaric Oxygen Potentiates Doxil Antitumor Efficacy by Promoting Tumor Penetration and Sensitizing Cancer Cells.

ABSTRACT: Hypoxia is a fundamental hallmark of solid tumors and helps contribute to chemotherapy resistance. Hyperbaric oxygen (HBO) therapy can overcome tumor hypoxia and promote chemotherapy antitumor efficacy; however, the simultaneous administration of some conventional chemotherapies, including doxorubicin (DOX), with HBO is considered an absolute contraindication. Here, DOX-loaded liposome (Doxil) is coadministered with HBO to assess the safety and efficacy of this combination treatment. By overcoming tumor hypoxia, HBO not only improves Doxil tumor penetration by decreasing the collagen deposition but also sensitizes tumor cells to Doxil. As a result, the combination treatment synergistically inhibits H22 tumor growth, with a tumor inhibition rate of 91.5%. The combination of HBO with Doxil shows neither extra side effects nor promotion of tumor metastasis. These results collectively reveal that the combination of HBO with Doxil is an effective and safe treatment modality. As both HBO and Doxil are routinely used, their combination could quickly translate to clinical trials for patients with hypoxic solid tumors.

SUBMITTER: Wu X

PROVIDER: S-EPMC6097095 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Hyperbaric Oxygen Potentiates Doxil Antitumor Efficacy by Promoting Tumor Penetration and Sensitizing Cancer Cells.

Wu Xian X Zhu Yanhong Y Huang Wei W Li Jingqiu J Zhang Bixiang B Li Zifu Z Yang Xiangliang X

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20180625 8

Hypoxia is a fundamental hallmark of solid tumors and helps contribute to chemotherapy resistance. Hyperbaric oxygen (HBO) therapy can overcome tumor hypoxia and promote chemotherapy antitumor efficacy; however, the simultaneous administration of some conventional chemotherapies, including doxorubicin (DOX), with HBO is considered an absolute contraindication. Here, DOX-loaded liposome (Doxil) is coadministered with HBO to assess the safety and efficacy of this combination treatment. By overcomi ...[more]

PMID: 30128223

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Project description:BackgroundHyperbaric oxygen therapy (HBOT) consists of intermittently administering 100% oxygen at pressures greater than one atmosphere absolute (ATA) in a pressure vessel. This technology has been used to treat a variety of diseases and has been described as helping patients who have delayed healing or established non-union of bony fractures. This is an update of a Cochrane Review first published in 2005, and previously updated in 2008.ObjectivesThe aim of this review is to assess the evidence for the benefit of hyperbaric oxygen treatment (HBOT) for the treatment of delayed bony healing and established non-union of bony fractures.Search methodsWe searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (July 2012), the Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7), MEDLINE (1946 to July Week 1 2012), EMBASE (1974 to 2012 July 16), CINAHL (1937 to 17 July 2012), the Database of Randomised Controlled Trials in Hyperbaric Medicine (accessed July 2012), the WHO International Clinical Trials Registry Platform (17 July 2012) and reference lists of articles.Selection criteriaWe aimed to include all randomised controlled trials comparing the clinical effects of HBOT with no HBOT (no treatment or sham) for healing of bony fractures and fracture non-unions.Data collection and analysisTwo review authors independently screened electronic search results, and all three authors independently performed study selection. We planned independent data collection and risk of bias assessment by two authors using standardised forms.Main resultsNo trials met the inclusion criteria. In this update, we identified three ongoing randomised controlled trials. Among the eight excluded studies were three randomised trials comparing HBOT with no treatment that included patients with fractures. One of these trials had been abandoned and the other two did not report on fracture healing outcomes.Authors' conclusionsThis systematic review failed to locate any relevant clinical evidence to support or refute the effectiveness of HBOT for the management of delayed union or established non-union of bony fractures. Good quality clinical trials are needed to define the role, if any, of HBOT in the treatment of these injuries. There are three randomised controlled trials underway and we anticipate these will help provide some relevant clinical evidence to address this issue in the future.

Project description:Tumor-targeting antibody (Ab)-fused cytokines, referred to as immunocytokines, are designed to increase antitumor efficacy and reduce toxicity through the tumor-directed delivery of cytokines. However, the poor localization and intratumoral penetration of immunocytokines, especially in solid tumors, pose a challenge to effectively stimulate antitumor immune cells to kill tumor cells within the tumor microenvironment. Here, we investigated the influence of the tumor antigen-binding kinetics of a murine interleukin 12 (mIL12)-based immunocytokine on tumor localization and diffusive intratumoral penetration, and hence the consequent antitumor activity, by activating effector T cells in immunocompetent mice bearing syngeneic colon tumors. Based on tumor-associated antigen HER2-specific Ab Herceptin (HCT)-fused mIL12 carrying one molecule of mIL12 (HCT-mono-mIL12 immunocytokine), we generated a panel of HCT-mono-mIL12 variants with different affinities (K D) mainly varying in their dissociation rates (k off) for HER2. Systemic administration of HCT-mono-mIL12 required an anti-HER2 affinity above a threshold (K D = 130 nM) for selective localization and antitumor activity to HER2-expressing tumors versus HER2-negative tumors. However, the high affinity (K D = 0.54 or 46 nM) due to the slow k off from HER2 antigen limited the depth of intratumoral penetration of HCT-mono-mIL12 and the consequent tumor infiltration of T cells, resulting in inferior antitumor activity compared with that of HCT-mono-mIL12 with moderate affinity of (K D = 130 nM) and a faster k off. The extent of intratumoral penetration of HCT-mono-mIL12 variants was strongly correlated with their tumor infiltration and intratumoral activation of CD4+ and CD8+ T cells to kill tumor cells. Collectively, our results demonstrate that when developing antitumor immunocytokines, tumor antigen-binding kinetics and affinity of the Ab moiety should be optimized to achieve maximal antitumor efficacy.

Dataset Information

Hyperbaric Oxygen Potentiates Doxil Antitumor Efficacy by Promoting Tumor Penetration and Sensitizing Cancer Cells.

Publications

Hyperbaric Oxygen Potentiates Doxil Antitumor Efficacy by Promoting Tumor Penetration and Sensitizing Cancer Cells.

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