Myo-Inositol Trispyrophosphate (ITPP) Benefits

Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2

Myo-Inositol Trispyrophosphate (ITPP) Benefits

  • Cancer therapy
  • Colon cancer
  • Hypoxia
  • Pharmacodynamics

Preventing tumor neovascularisation is one of the strategies recently developed to limit the dissemination of cancer cells and apparition of metastases.

Although these approaches could improve the existing treatments, a number of unexpected negative effects have been reported, mainly linked to the hypoxic condition and the subsequent induction of the pro-oncogenic hypoxia inducible factor(s) resulting from cancer cells’ oxygen starvation. Here, we checked in vivo on colon cancer cells an alternative approach.

It is treatment with myo-inositol trispyrophosphate (ITPP), a molecule that leads to increased oxygenation of tumors. We provide evidence that ITPP increases the survival of mice in a model of carcinomatosis of human colon cancer cells implanted into the peritoneal cavity. ITPP also reduced the growth of subcutaneous colon cancer cells xenografted in nu/nu mice.

In the subcutaneous tumors, ITPP stimulated the expression of the homeobox gene Cdx2 that is crucial for intestinal differentiation and that also has an anti-tumoral function. On this basis, human colon cancer cells were cultured in vitro in hypoxic conditions. Hypoxia was shown to decrease the level of Cdx2 protein, mRNA and the activity of the Cdx2 promoter.

This decline was unrelated to the activation of HIF1α and HIF2α by hypoxia. However, it resulted from the activation of a phosphatidylinositol 3-kinases- mitogen-activated protein kinase pathway, as assessed by the fact that LY294002 and U0126 restored high Cdx2 expression in hypoxia.

Corroborating these results, U0126 recapitulated the increase of Cdx2 triggered by ITPP in subcutaneous colon tumor xenografts. The present study provides evidence that a chemical compound that increases oxygen pressure can antagonize the hypoxic setting and reduce the growth of human colon tumors implanted in nu/nu mice.

Hypoxia is an aggravating factor in cancer that stimulates angiogenesis and consequently the intake of nutrients for tumor growth, and that also opens routes for invasive cells to disseminate the primary tumor to form metastases. On this basis, chemotherapy with drugs targeting the vascular endothelial growth factor pathway provides some benefit for the patients.

However, a number of unexpected limitations have been encountered, in particular related to the fact that inhibiting vessel formation in tumors starves malignant cells from nutrients and oxygen, which subsequently activates the hypoxia response pathway(s) and the pro-oncogenic hypoxia inducible factor-1 (HIF1).

1 We have previously described myo-inositol trispyrophosphate (ITPP), a molecule that increases the release of bound dioxygen from haemoglobin in vitro and improves oxygen tension under hypoxic conditions in vivo.

2 This molecule ameliorates the exercise capacity of transgenic mice with severe heartfailure3 and inhibits angiogenesis in a chorioallantoid membrane model.

4 Of note, when used on cancer models, ITPP was shown to reduce the growth of xenografted glioma and leads to the eradication of early liver tumors,4, 5 opening the possibility that increasing the oxygen load could represent a contrasting alternative to anti-vascular endothelial growth factor therapy in cancer.

Colorectal cancer is the third cause of death by cancer and one of the leading types of cancer in which anti-angiogenic therapy is being evaluated. Here, we report beneficial context-dependent effects of ITPP in colon cancer models. We further show that the intestine-specific homeobox gene, Cdx2, which is crucial for homeostasis of the gut epithelium6 and also exhibits anti-tumor activity,7, 8 is a downregulated target of hypoxia in colon cancer cells, while being upregulated by ITPP.

To address whether ITPP has any effect on colon tumour growth, we first used the intraperitoneal carcinomatosis model of HT29 cells implanted in the abdominal cavity of athymic nu/nu mice.9 Two weeks after the injection of 107 cells, a series of 10 mice were treated weekly with ITPP at 1.5 or 2 mg/g body weight or saline buffer.

As a positive control for drug therapy, one series of mice was treated with Capecitabine at 0.25 mg/g body weight. The mortality was evaluated during 9 weeks of treatment and surviving mice were then euthanized and autopsied. Both doses of ITPP reduced the mortality as compared to NaCl, slightly better than Capecitabine (Figure 1a).

At the end of the treatment two mice survived in the NaCl group, whereas five, five and four mice survived in the groups treated, respectively, with ITPP 1.5 mg/g, ITPP 2 mg/g and Capecitabine 0.25 mg/g. One of the two NaCl-treated mice was tumor free, but this ratio rose to 3/4 in Capecitabine-treated mice and even to 4/5 and 5/5 in mice treated with ITPP at 1.5 and 2 mg/g.

These data indicate that ITPP antagonizes colon cancer growth in the model of intraperitoneal carcinomatosis.

Figure 1

In vivo effect of ITPP on cancer cells xenografted in nu/nu mice. (a) Survival curve in series of 10 six-week old nu/nu mice (Charles River) xenografted intraperitoneally with 107 HT29 cells each, and treated with ITPP (ISIS Strasbourg, 2 mg/g of body weight), Capecitabine (CPT, University Hospital of Strasbourg, 0.25 mg/g of body weight) or NaCl 0.9%.

For clarity, the results obtained with ITPP at 1.5 mg/g of body weight were omitted here because they were similar to those with ITPP at 2 mg/g body weight. Drugs were administered weekly, starting 2 weeks after cell injection (black arrows), and living mice were killed after the ninth week of treatment.

(b) Subcutaneous growth of HT29 cells implanted in nu/nu mice (2 × 106 cells per site of injection, 2 sites of injection per mouse, 6 mice per group), treated weekly with ITPP at 2 mg/g of body weight starting on the day of cell injection (ITPP) or 2 weeks later (ITPP*), or with NaCl.

Tumor size was measured with calliper, and volumes were calculated with the formula: (L × W2) x 0.5, where L is length and W is width. *P

Source: https://www.nature.com/articles/onc2012445

ITPP (Myo-Inositol Trispyrophosphate)

Myo-Inositol Trispyrophosphate (ITPP) Benefits

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Myo-Inositol Trispyrophosphate (ITPP) is a relatively new compound that improves the ability of haemoglobin in red blood cells to release oxygen into tissues. It has the chemical formula C6H15O15P3 and the molecular weight 420.096 g/mol.

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Myo-Inositol Trispyrophosphate (ITPP) is a recently discovered compound Myo-Inositol with significance in its ability to alter the oxygen-disassociation curve for haemoglobin in red blood cells. ITPP is of great interest to medical researchers studying the pathology of diseases related to hypoxia (low oxygen levels). Anecdotally, it may have similar effects to other energizing products.  

Where to Buy ITPP Online?

LiftMode offers a variety of unit sizes of Myo-Inositol Trispyrophosphate (ITPP), including a 1 gram sample, 2-gram (0.07 Oz), and 5 grams (0.18 Oz) unit sizes.  

All our products ship with a certificate of analysis from 3rd-party independent laboratories and all orders are covered by our 90-days refund/reshipment policy to ensure the highest quality.

Shipping restrictions: No shipping restrictions currently apply to this product and we are able to ship internationally. At checkout, the available shipping options for your location will be available.

Nomenclature:

Myo-Inositol Trispyrophosphate (ITPP) is known by a number of alternative names including:

Inositol TripyrophosphateInositol 1,4,5-trisphosphateMyo Inositol Trispyrophosphate
Sometimes confused for: Inositol Triphosphate (IT3)[(1R,2S,3R,4R,5S,6R)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphateIP3

Scientific Consensus:

This is a relatively new product and there is very limited research on its effects and benefits in humans. Further research is necessary to fully understand the significance of its effects and adverse effects. Use with caution

DO NOT EXCEED THE RECOMMENDED SERVING SIZE. Use with caution. Do not use if pregnant or breastfeeding.

PLEASE NOTE: ITPP is currently on the World Anti-Doping Agency list, and may NOT be used by professional athletes.

Disclaimer:

All dietary supplements have risks. Please ensure that you are familiar with the latest research on effects, side effects, benefits, and uses of a supplement before buying it.

Store in a cool, dry place. Keep reach of children. If you have any underlying medical conditions or are taking any medication, please consult a medical professional before using this supplement. 

These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

How We Research Our Content

Our content is written using meticulous research methods and claims are backed by links to scientific references, wherever possible. The author and editors of Liftmode's Research Team have strong academic backgrounds in microbiology, physiology, and biochemistry.

Content Updated On: October 17, 2019

References:

  • Duarte , C. D., Greferath , R., Nicolau , C., & Lehn, J.-M. (2010). Myo-inositol Trispyrophosphate: A Novel Allosteric Effector of Hemoglobin with High Permeation Selectivity across the Red Blood Cell Plasma Membrane. ChemBioChem, 11(18), 2543–2548. doi:10.1002/cbic.201000499
  • Lam, G., Zhao, S., Sandhu, J., Yi, R., Loganathan, D., & Morrissey, B. (2013). Detection of myo-inositol tris pyrophosphate (ITPP) in equine following an administration of ITPP. Drug Testing and Analysis, 6(3), 268–276. doi:10.1002/dta.147
  • Görgens, C., Guddat, S., Schänzer, W., & Thevis, M. (2014). Screening and confirmation of myo-inositol trispyrophosphate (ITPP) in human urine by hydrophilic interaction liquid chromatography high resolution / high accuracy mass spectrometry for doping control purposes. Drug Testing and Analysis, 6(11-12), 1102–1107. doi:10.1002/dta.1700
  • Raykov, Z., Grekova, S. P., Bour, G., Lehn, J. M., Giese, N. A., Nicolau, C., & Aprahamian, M. (2013). Myo-inositol trispyrophosphate-mediated hypoxia reversion controls pancreatic cancer in rodents and enhances gemcitabine efficacy. International Journal of Cancer, 134(11), 2572–2582. doi:10.1002/ijc.28598
  • Kieda, C., Greferath, R., Crola Da Silva, C., Fylaktakidou, K. C., Lehn, J.-M., & Nicolau, C. (2006). Suppression of hypoxia-induced HIF-1 and of angiogenesis in endothelial cells by myo-inositol trispyrophosphate-treated erythrocytes. Proceedings of the National Academy of Sciences, 103(42), 15576–15581. doi:10.1073/pnas.0607109103

Source: https://liftmode.com/energizing/myo-inositol-trispyrophosphate-itpp.html

Doping Control: Myo-inositol Trispyrophosphate (ITPP)

Myo-Inositol Trispyrophosphate (ITPP) Benefits

Allosteric effectors that interact with hemoglobin bind to the hemoglobin molecules, thereby regulating oxygen uptake and release.

Therapeutic drugs that illicit this response carry significant abuse potential, since increased oxygenation of the tissues improves athletic performance.

The novel allosteric effector myo-inositol trispyrophosphate (ITPP) is currently in phase 1 clinical trials for chronic heart failure and cancer applications (under the designation of OXY111A).

This compound already has been used for performance enhancement in the horse racing industry and is readily available online in the form of oral nutritional supplements and even injectable solutions. ITPP is included on the World Anti-Doping Agency’s prohibited list of substances for human athletes; however, no method yet exists to detect this substance in human urine.

For this reason, Görgens et al. (2014) set out to develop a simple, robust screening and confirmation protocol for ITPP in human urine.

1 Because the compound is highly polar in nature and therefore unsuited for reversed-phase liquid chromatography, the team turned to hydrophilic interaction liquid chromatography (HILIC) and tandem mass spectrometry (MS/MS) for the analysis of human urine spiked with ITPP and internal standard ITPP-d6.

The researchers used an Accela 1250 quaternary pump, PAL autosampler, and Q Exactive hybrid quadrupole-Orbitrap mass spectrometer (all Thermo Scientific) to detect the precursor ions for both ITPP and the internal standard (m/z 301.9065 and 304.

9253, respectively), as well as the diagnostic product ions (m/z 78.9580, 158.9243, and 524.8550). They also developed a confirmation protocol for suspicious urine samples, using a weak anion exchange solid-phase extraction method (WAX-SPE).

The team determined that their method is specific for both screening and confirmation, with good precision over a concentration range of 50–500 ng/mL and 5–125 ng/mL for screening and confirmation, respectively.

They estimated the lower limits of detection to be 15 ng/mL and 1 ng/mL, respectively, for screening and confirmation.

They also report no significant decrease in ITPP concentration within the urine matrix after three months of storage, consistent with the mandatory doping control storage period.

Görgens et al. present their method as a sensitive, reliable protocol for screening and confirming the presence of ITPP in human urine. They note that HILIC separation renders their screening method fast and time-effective, with virtually no sample preparation.

The additional option of confirmation via solid-phase extraction increases the sensitivity and versatility of the total protocol.

The team further posits that the flexible nature of their approach may make it suitable for other screening applications, particularly those with highly polar analytes.

Reference

1. Görgens, C., et al. (2014, July) “Screening and confirmation of myo-inositol trispyrophosphate (ITPP) in human urine by hydrophilic interaction liquid chromatography high resolution / high accuracy mass spectrometry for doping control purposes,” Drug Testing and Analysis, doi: 10.1002/dta.1700.

Post Melissa J. Mayer. Melissa is a freelance writer who specializes in science journalism. She possesses passion for and experience in the fields of proteomics, cellular/molecular biology, microbiology, biochemistry, and immunology. Melissa is also bilingual (Spanish) and holds a teaching certificate with a biology endorsement.

Source: https://www.thermofisher.com/blog/proteomics/doping-control-myo-inositol-trispyrophosphate-itpp/

Myo-Inositol Trispyrophosphate (ITPP) Benefits

Myo-Inositol Trispyrophosphate (ITPP) Benefits

Myo-Inositol Trispyrophosphate (ITPP) is a substance that may have performance-enhancing and anti-cancer properties, although no studies in humans have been performed. ITPP is also banned in most professional sports. Read on to learn more about this compound and the research behind it.

What is Myo-Inositol Trispyrophosphate?

Myo-Inositol Trispyrophosphate (ITPP) is a synthetic compound that has become popular for its potential as a performance-enhancing substance for athletes and in horse racing [1, 2].

ITPP is an inositol phosphate, which is a group of compounds that play an important role in cellular function and cell signalling [3].

ITPP works by binding to the membrane of red blood cells (hemoglobin), which promotes the release of oxygen from the cells [3].

According to some, this increase in oxygen delivery may improve muscle function and activity. There’s also evidence from animal studies that ITPP may have anti-cancer properties, although no studies in humans have been performed [4, 5].

ITPP is banned in most professional sports and horse racing. Researchers have developed ways to detect this substance in the urine of humans and horses [1, 2].

Animal and Cell Research

No clinical evidence supports the use of ITPP for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

It’s also important to note that ITPP is on the World Anti-Doping Agency’s prohibited list of substances [6].

1) Improving Hypoxia

ITPP’s potential ability to improve the oxygen release capacity of red blood cells has led some researchers to explore its effect on hypoxia, a condition where tissues in the body do not receive enough oxygen.

A sign of hypoxia is angiogenesis, which is the formation of new blood vessels. The body naturally accelerates angiogenesis during hypoxia in order to supply more oxygen to tissues [7].

A cell study found that ITPP may reduce angiogenesis and other markers of hypoxia, including VEGF and hypoxia-inducible factor 1alpha [7].

Another study in mice suggests that ITPP administration may decrease the ability of red blood cells to bind oxygen and increases the delivery of oxygen to tissues [8].

2) Improving Exercise Capacity

According to a mouse study, ITPP may increase maximal exercise capacity in a dose-related manner, with a maximum increase of 57% being reported in the study [8].

In a study looking at mice with severe heart failure, ITPP administration also increased exercise capacity according to treadmill tests [8].

Research in mice also suggests that ITPP may improve exercise when administered orally or through injection [9].

3) Anti-cancer Properties

ITPP has not been shown to treat or prevent cancer. The potential effect of ITPP in cancer has only been studied in animals and cells.

It’s important to note that many substances have anti-cancer effects in cells, even toxic chemicals. This doesn’t necessarily mean that they have medical value. On the contrary, most substances (natural or synthetic) that are researched in cancer cells fail to pass further animal studies or clinical trials due to a lack of safety or efficacy.

As mentioned earlier, one of the effects of hypoxia (low oxygen levels) is angiogenesis, or the formation of new blood vessels. Angiogenesis is a normal and important part of growth and development for the body, but it can become a problem in cancer. Angiogenesis can also promote the growth of tumors and help cancer cells metastasize (spread to other locations) [10].

A number of animal and cell studies suggest that ITPP may have anti-cancer effects by preventing hypoxia and angiogenesis. Researchers suggest that this effect may decrease tumor growth and the risk of metastasis [4, 5, 11].

Animal and cell studies have studied the effect of ITPP on various types of cancer, including:

  • Pancreatic cancer [12]
  • Colon cancer [4, 13, 14]
  • Liver cancer [15, 16]
  • Glioma, a type of tumor that affects the brain and spinal cord [5, 11]

However, there is some conflicting evidence. One rat study found that ITPP had no effect on survival in glioblastoma tumors. Another rat study also found that ITPP had no effect on glioblastoma, and may even reduce the effectiveness of radiation therapy [17, 18].

Side Effects, Drug Interactions, and Dosage

There is no information on the safety of ITPP. The side effects, drug interactions, and optimal dose of ITPP are all unknown.

Caution

ITPP is banned in professional sports and is on the World Anti-Doping Agency’s prohibited list of substances [6].

Source: https://selfhacked.com/blog/itpp/

Failure of Inositol Trispyrophosphate to Enhance Highly Effective Radiotherapy of GL261 Glioblastoma in Mice

Myo-Inositol Trispyrophosphate (ITPP) Benefits

  1. SUJATHA IYENGAR and
  2. DAVID SCHWARTZ⇑
  1. Jurist Center for Research, Hackensack University Medical Center, Hackensack, NJ, U.S.A.
  1. Correspondence to: David Schwartz, Jurist Center for Research, Hackensack University Medical Center, 40 Prospect Ave, Hackensack, NJ 07601, U.S.A. Tel: +1 4437170325, e-mail: dschwart{at}fastmail.fm

Background/Aim: Inositol trispyrophosphate (ITPP), reported to cure hepatomas in a preclinical rat model and to have beneficial effects in several other solid tumor models, is currently in clinical trial for liver cancer.

We investigated whether aggressive glioblastomas could be effectively treated with ITPP alone or in combination with radiation therapy (RT). Materials and Methods: C57Bl/6 mice were intracranially injected with syngeneic GL261 glioblastoma cells and treated with hypofractionated radiation (5 Gy × 3), ITPP, or both.

Tumors were followed by imaging, and mice sacrificed due to morbidity or at 90 days, with microscopic examination of brain sections. Results: RT alone significantly prolonged survival, whereas ITPP alone did not. Surprisingly, ITPP appeared to reduce the effectiveness of RT when added in combination.

Conclusion: ITPP was ineffective as monotherapy for glioblastoma and appeared to interfere with the beneficial impact of RT.

Glioblastoma multiforme (GBM) is among the most difficult to treat malignancies. In part, this is due to the essential function of the brain, the difficulties of treating a tumor within a confined space, and the problems of drug penetration through the blood–brain barrier.

Additionally, it has long been noted that the relative hypoxia within brain tumors may interfere with the efficacy of radiation therapy (RT) and various antitumor drugs, while promoting the survival of cancer stem cells (1-5). Disturbingly, radiation has been implicated in triggering new mechanisms of GBM invasiveness involving activation of Rho kinase (6).

Nevertheless, radiation remains a mainstay of GBM treatment, providing up to several months of delayed progression (7-10).

We reasoned that reversal of tumor hypoxia would, in theory, be highly beneficial, slowing or reversing hypoxia-inducible factor (HIF)-mediated changes that promote tumor progression, and enhancing the response to drugs and RT. To this end, we employed a novel candidate drug, inositol trispyrophosphate (ITPP).

This small molecule is actively transported by the erythrocyte membrane 3 anion transporter protein into red blood cells, where it binds to hemoglobin allosterically, with higher affinity for deoxyhemoglobin.

The reported result is a ‘right shift’ of the oxygen-hemoglobin dissociation curve, such that more oxygen is released from hemoglobin at lower ambient oxygen concentrations. Thus, the hypoxia of tumor regions should be partially reversed.

ITPP has proven highly active in several pre-clinical models of solid tumors, with evidence of reduced tumor region hypoxia and reduced expression of hypoxia-inducible factor (HIF) and HIF-regulated pathways (11-15).

Phosphatase and tensin homolog (PTEN) levels were also shown to be elevated after ITPP treatment (11), and growth of glioma cells in chorionic allantoic membrane cultures was inhibited (14). ITPP is currently in clinical trials at the University of Zurich, for liver and pancreatic cancer. We hypothesized that ITPP would also be beneficial in combination with RT of gliomas.

The GL261 cell line is a C57BL/6-derived aggressive astrocytoma that has been used in many studies of orthotopic syngeneic modeling of glioblastoma. It is moderately radiosensitive, and can be immunogenic under some conditions (16-20). In particular, Zeng et al.

showed that non-curative irradiation can be combined with the immune checkpoint inhibitor, antibody to programmed death receptor (PD1), to generate highly protective immunity against established GL261 tumors (20).

Since physiological normoxia, checkpoint inhibitors, should support effector immunity and reduce hypoxia-associated tumor tolerance, ITPP and RT were assessed separately, and in combination, as treatments for established GL261 tumors in the C57BL/6 orthotopic syngeneic model.

Mice. C57BL6 female mice were purchased from Charles River Laboratories (Wilmington, MA, USA), housed in the Beaumont Radiation Animal Facility (Royal Oak, MI, USA), and used at 9-11 weeks, at which time they weighed 25-30 g. This work was performed under Oakland University IACUC approval # AL-14-05.

Tumor injection. Twenty female C57Bl/6 mice (Jackson Laboratories, Bar Harbor, ME, USA) were implanted intracranially with 1×105 GL261 cells (National Cancer Institute Repository, Frederick, MD, USA) in 2 μl of sterile phosphate-buffered saline on day 0.

Mice were 14 weeks of age at the start of experiment and weighed ~22 g. The implant site was 1 mm posterior to the bregma and 1 mm lateral of the midline suture on the left side of the brain.

Small alterations in position were made to avoid obvious vasculature when possible. For implantation, a 26G Hamilton syringe was inserted 4 mm into the brain and then withdrawn to 3.5 mm for injection, which was performed over several minutes.

The cranial bore-hole was sealed with bone wax following withdrawal of the needle and the incision closed with surgical glue.

Magnetic resonance imaging (MRI). Seven days post implantation, and at weekly intervals thereafter, animals received diluted Multihance (Bracco Diagnostics, Inc., Cranbury, NJ, USA) i.v.

and underwent contrast-enhanced MRI under anesthesia.

Fast spin-echo T1- and T2-weighted images were acquired at 0 and 5 minutes post-contrast injection, and tumor volumes were determined by delineating areas of contrast enhancement.

Group distribution of animals.

In order to ensure statistically similar tumor burdens among all four groups of mice, animals were ranked for tumor volume, and then assigned to one of four treatment groups (placebo, RT, ITPP, or RT plus ITPP) using an algorithm that minimized differences among means and SEMs among groups. One-week mean tumor volumes among groups post-assignment ranged from 5.6 to 6.6 mm3, and were not statistically different among groups.

Treatments, monitoring, and statistical analysis. On the eighth day post-tumor implantation, ITPP treatments were begun, using an i.p. dose of 1 g/kg every 4 days five times. This dose is within the range that has proven effective against liver and colon tumors in mice and rats (11-14).

RT was initiated in the RT and RT plus ITPP groups one day later (day 9). We used a hypofractionated dose of 5 Gy every 4 days three times, rather than a single dose Zeng et al.

(19), or the more typical daily or every-other-day fractionated doses used in tumor RT models, including models where non-metastasizing GL261 tumors are established and treated in the flanks of mice (21). Radiation was delivered to the whole head using a Faxitron cabinet irradiator, at a rate of 0.

25 cGy/min to body-shielded mice. A total of 15 Gy was delivered in three 5 Gy/day doses spaced 4 days apart (i.e. over an eight-day window from day 9-17 post-tumor injection).

In addition to the MRI, mice were monitored daily for weight and signs of neurological impairment, including: lethargy, poor grooming, asymmetric gait, hunched posture, head position asymmetry, any abnormal movements.

Mice exhibiting more than 20% weight loss, or progression of any of the above signs for more than 2-3 days were sacrificed. Mice surviving without signs for more than 90 days were sacrificed by cervical dislocation after xylazine/ketamine overdose.

Survival curves were analyzed by the Gehan-Breslow-Wilcoxon method.

Sacrifice and brain histopathology. Upon sacrifice, brain tissue was collected from all animals and fixed in paraformaldehyde for further histological studies. Tissue samples were then blocked and hematoxylin and eosin (H&E) slides stained for each sample. Images were obtained at ×10 and ×40 magnification and examined quantitatively for regions of normal brain, tumor, and hemorrhage.

Figure 1 summarizes the group survival curves. Control mice receiving GL261 cells died or were sacrificed due to neurological signs between 19 and 27 days post-tumor implant (mean survival=26.5 days).

Disappointingly, mice receiving ITPP treatment, starting on day 8 post-tumor implantation, showed no improvement in survival, with animals dying between days 21 and 25 (mean=23 days). Surprisingly, strong beneficial results were seen for the group treated with RT only, which had the longest mean survival time of 64 days.

Two animals survived the full 91-day observation period, with stabilization or reduction in tumor size by MRI after initial growth.

One animal sacrificed at day 49 due to weight loss, pallor, hunched posture and poor ambulation, showed no evidence of residual tumor on H&E histopathology examination of the brain (possibly dying from other causes after clearing tumor burden). The two mice sacrificed in good health at 91 days had no histopathological evidence of tumor on H&E staining (Figure 2, upper right).

When added to RT, ITPP failed to confer any survival benefit.

Indeed, the mean survival time for the group treated with RT plus ITPP (46 days) was borderline significantly less than that of the group treated with RT only (p=0.06).

One mouse receiving the combined RT plus ITPP therapy survived the full 91-day observation period and had no histopathological evidence of tumor in brain sections.

Tumor volumes assessed by MRI showed significant effects of RT, with lower volumes at different post-injection time points. As expected, mean tumor volume growth during the first 6-8 weeks post-implant corresponded inversely with group survival rates (Figure 3).

Interestingly, ITPP-treated animals, as a group, were deemed terminal at lower tumor volumes (94 mm3) than control animals receiving saline (136 mm3). This was also true for tumor volumes in RT-treated mice also receiving ITPP (87 mm3) vs.

those receiving only RT (177 mm3) sacrificed for morbidity. The lower tumor volumes by MRI at death were generally consistent with smaller areas of tumor-involved brain upon histopathological examination.

It is possible that these low tumor volume deaths reflect microscopic satellite areas of invasive spread not detected with MRI or histopathology.

Two key points emerge from this study. Firstly, contrary to expectations, ITPP was not beneficial with respect to survival, and may have been detrimental when added to RT.

Secondly, a total of 15 Gy given in three equal 5 Gy doses at 4-day intervals, starting 9 days after tumor injection, was highly protective, with an overall ‘cure’ rate of 30% among 10 mice receiving RT as a component of therapy (with or without ITIPP). In addition, one mouse receiving RT alone died without MRI or histopathological evidence of tumor.

If this animal cleared its tumor, as histopathology suggests, then 40% of mice had no residual tumor following RT. This degree of tumor regression has not previously been described for RT of orthotopic GL261 tumors.

View larger version:

Figure 1.

Survival curves for mice orthotopically injected with GL261 cells. The median survival compared by the Grehan-Breslow-Wilcoxon test) of control mice (26.5 days) was not significantly different from those treated with inositol trispyrophosphate (ITPP, 23 days). Radiotherapy (RT) significantly extended mean survival (64 days, p

Source: http://ar.iiarjournals.org/content/37/3/1121.full

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

Myo-Inositol Trispyrophosphate (ITPP) Benefits

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378184/

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