Impact of <i>myo</i>‐inositol trispyrophosphate (ITPP) on tumour oxygenation and response to irradiation in rodent tumour models

Tran, Ly-Binh-An; Cao-Pham, Thanh-Trang; Jordan, Bénédicte F.; Deschoemaeker, Sofie; Heyerick, Arne; Gallez, Bernard

doi:10.1111/jcmm.14092

Cited by 11 publications

(8 citation statements)

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“…Our study results are similar to those obtained by Tran et al [ 33 ], who measured pO 2 in six murine and two rat tumor models, and demonstrated an increase in tumor pO 2 by 7–10 mm Hg for up 72–96 h with slightly different ITPP protocols. They also demonstrated radiosensitization to single-dose radiation, similar to Grgic et al, who demonstrated increased DNA damage after ITPP and radiation [ 42 ].…”

Section: Discussionsupporting

confidence: 92%

“…A relatively rich vascular network is present in young tumors, deteriorating quickly with tumor growth. Even though pO 2 in young 4T1 tumors may be high ( Fig 2 ), it declines rapidly, rendering the tumors hypoxic [ 33 , 41 ]. The ITPP dosing frequency needs to be adjusted to tumor growth rate, with shorter intervals in fast-growing tumors.…”

Section: Discussionmentioning

confidence: 99%

“…B16F10 tumors were treated with 6 ITPP injections on either 5, 6, 11, 12, 17, 18 or 5, 6, 12, 13, 19, 20 days after tumor inoculation, all as an intraperitoneal dose of 2 g/kg. These treatment protocols were designed based on earlier results by Tran et al [ 33 ] and pilot experiments. The treatment schedules were adjusted to the tumor growth rate.…”

Section: Methodsmentioning

confidence: 99%

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Oxygen therapeutic window induced by myo-inositol trispyrophosphate (ITPP)–Local pO2 study in murine tumors

et al. 2023

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Hypoxia, an inevitable feature of locally advanced solid tumors, has been known as an adverse prognostic factor, a driver of an aggressive phenotype, and an unfavorable factor in therapies. Myo-inositol trispyrophosphate (ITPP) is a hemoglobin modifier known to both increase O2 release and normalize microvasculature. Our goal was to measure the tumor oxygen partial pressure dynamic changes and timing of the therapeutic window after ITPP systemic administration. Two syngeneic tumor models in mice, B16 melanoma and 4T1 breast carcinoma, were used, with varying ITPP dose schedules. Tissue oxygenation level was measured over several days in situ in live animals by Electron Paramagnetic Resonance oximetry with implanted OxyChip used as a constant sensor of the local pO2 value. Both B16 and 4T1 tumors became more normoxic after ITPP treatment, with pO2 levels elevated by 10–20 mm Hg compared to the control. The increase in pO2 was either transient or sustained, and the underlying mechanism relied on shifting hypoxic tumor areas to normoxia. The effect depended on ITPP delivery intervals regarding the tumor type and growth rate. Moreover, hypoxic tumors before treatment responded better than normoxic ones. In conclusion, the ITPP-generated oxygen therapeutic window may be valuable for anti-tumor therapies requiring oxygen, such as radio-, photo- or immunotherapy. Furthermore, such a combinatory treatment can be especially beneficial for hypoxic tumors.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Oxygen therapeutic window induced by myo-inositol trispyrophosphate (ITPP)–Local pO2 study in murine tumors

et al. 2023

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“…Another strategy to increase the oxygen delivery without altering the perfusion is to promote the release of oxygen by hemoglobin (Hb). It has been shown that allosteric effectors (such as efaproxiral or myo-inositol trispyrophosphate) binding to Hb results in a decreased hemoglobin-oxygen (Hb-O 2 ) affinity and an increased tumor oxygenation (Teicher et al, 1998;Khandelwal et al, 1999;Amorino et al, 2001;Hou et al, 2004;Hou et al, 2005;Suh et al, 2006;Hou et al, 2007;Scott et al, 2007;Aprahamian et al, 2011;Limani et al, 2016;Tran et al, 2019;Cao-Pham et al, 2020). The increases in regulated oxygen-releasing capacity of red blood cells has been shown to potentiate the response to irradiation (Teicher et al, 1998;Khandelwal et al, 1999;Amorino et al, 2001;Suh et al, 2006;Hou et al, 2007;Scott et al, 2007;Tran et al, 2019).…”

Section: Decreasing Tumor Hypoxia By Improving the Oxygen Deliverymentioning

confidence: 99%

“…It has been shown that allosteric effectors (such as efaproxiral or myo-inositol trispyrophosphate) binding to Hb results in a decreased hemoglobin-oxygen (Hb-O 2 ) affinity and an increased tumor oxygenation (Teicher et al, 1998;Khandelwal et al, 1999;Amorino et al, 2001;Hou et al, 2004;Hou et al, 2005;Suh et al, 2006;Hou et al, 2007;Scott et al, 2007;Aprahamian et al, 2011;Limani et al, 2016;Tran et al, 2019;Cao-Pham et al, 2020). The increases in regulated oxygen-releasing capacity of red blood cells has been shown to potentiate the response to irradiation (Teicher et al, 1998;Khandelwal et al, 1999;Amorino et al, 2001;Suh et al, 2006;Hou et al, 2007;Scott et al, 2007;Tran et al, 2019). It has been suggested that the beneficial aspect of allosteric effectors could also be mediated by the suppression of HIF-1α and to down-regulation of HIFinducible genes such as VEGF (Aprahamian et al, 2011).…”

Section: Decreasing Tumor Hypoxia By Improving the Oxygen Deliverymentioning

confidence: 99%

The Role of Imaging Biomarkers to Guide Pharmacological Interventions Targeting Tumor Hypoxia

Gallez

2022

Front. Pharmacol.

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Hypoxia is a common feature of solid tumors that contributes to angiogenesis, invasiveness, metastasis, altered metabolism and genomic instability. As hypoxia is a major actor in tumor progression and resistance to radiotherapy, chemotherapy and immunotherapy, multiple approaches have emerged to target tumor hypoxia. It includes among others pharmacological interventions designed to alleviate tumor hypoxia at the time of radiation therapy, prodrugs that are selectively activated in hypoxic cells or inhibitors of molecular targets involved in hypoxic cell survival (i.e., hypoxia inducible factors HIFs, PI3K/AKT/mTOR pathway, unfolded protein response). While numerous strategies were successful in pre-clinical models, their translation in the clinical practice has been disappointing so far. This therapeutic failure often results from the absence of appropriate stratification of patients that could benefit from targeted interventions. Companion diagnostics may help at different levels of the research and development, and in matching a patient to a specific intervention targeting hypoxia. In this review, we discuss the relative merits of the existing hypoxia biomarkers, their current status and the challenges for their future validation as companion diagnostics adapted to the nature of the intervention.

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Combined endogenous MR biomarkers to assess changes in tumor oxygenation induced by an allosteric effector of hemoglobin

Cao-Pham

Tran‐Ly‐Binh

Heyerick³

et al. 2019

NMR in Biomedicine

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Hypoxia is a crucial factor in cancer therapy, determining prognosis and the effectiveness of treatment. Although efforts are being made to develop methods for assessing tumor hypoxia, no markers of hypoxia are currently used in routine clinical practice. Recently, we showed that the combined endogenous MR biomarkers, R1 and R2*, which are sensitive to [dissolved O2] and [dHb], respectively, were able to detect changes in tumor oxygenation induced by a hyperoxic breathing challenge. In this study, we further validated the ability of the combined MR biomarkers to assess the change in tumor oxygenation induced by an allosteric effector of hemoglobin, myo‐inositol trispyrophosphate (ITPP), on rat tumor models. ITPP induced an increase in tumor pO2, as observed using L‐band electron paramagnetic resonance oximetry, as well as an increase in both R1 and R2* MR parameters. The increase in R1 indicated an increase in [O2], whereas the increase in R2* resulted from an increase in O2 release from blood, inducing an increase in [dHb]. The impact of ITPP was then evaluated on factors that can influence tumor oxygenation, including tumor perfusion, saturation rate of hemoglobin, blood pH and oxygen consumption rate (OCR). ITPP decreased blood [HbO2] and significantly increased blood acidity, which is also a factor that right‐shifts the oxygen dissociation curve. No change in tumor perfusion was observed after ITPP treatment. Interestingly, ITPP decreased OCR in both tumor cell lines. In conclusion, ITPP increased tumor pO2 via a combined mechanism involving a decrease in OCR and an allosteric effect on hemoglobin that was further enhanced by a decrease in blood pH. MR biomarkers could assess the change in tumor oxygenation induced by ITPP. At the intra‐tumoral level, a majority of tumor voxels were responsive to ITPP treatment in both of the models studied.

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Impact of myo‐inositol trispyrophosphate (ITPP) on tumour oxygenation and response to irradiation in rodent tumour models

Cited by 11 publications

References 56 publications

Oxygen therapeutic window induced by myo-inositol trispyrophosphate (ITPP)–Local pO2 study in murine tumors

Oxygen therapeutic window induced by myo-inositol trispyrophosphate (ITPP)–Local pO2 study in murine tumors

The Role of Imaging Biomarkers to Guide Pharmacological Interventions Targeting Tumor Hypoxia

Combined endogenous MR biomarkers to assess changes in tumor oxygenation induced by an allosteric effector of hemoglobin

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