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Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients' bed.

Ferrari S, Perut F, Fagioli F, Brach Del Prever A, Meazza C, Parafioriti A, Picci P, Gambarotti M, Avnet S, Baldini N, Fais S - J Transl Med (2013)

Bottom Line: Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness.An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors.Notably, no significant increase in toxicity was recorded in PPI treated patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Anti-Tumour Drugs Section Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy. stefano.fais@iss.it.

ABSTRACT

Background: Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H +-rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma.

Method: MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin.

Results: Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients.

Conclusion: This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy.

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Related in: MedlinePlus

In vivo effects of ESOM on tumor growth in CB.17 SCID/SCID mice. Mice were engrafted with Saos-2 cells via s.c. injection in the right flank. At the time of tumor appearance (approximately 7–10 days after injection), mice were left untreated or were pre-treated with 25 mg/kg of ESOM 24 hrs before the i.p. injection of CDP or treated with CDP alone. Tumor size was measured three times per week, and volume was calculated as described in the “Methods” section. The histograms represent mean +/− 95% confidence intervals of tumor weight.
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Figure 2: In vivo effects of ESOM on tumor growth in CB.17 SCID/SCID mice. Mice were engrafted with Saos-2 cells via s.c. injection in the right flank. At the time of tumor appearance (approximately 7–10 days after injection), mice were left untreated or were pre-treated with 25 mg/kg of ESOM 24 hrs before the i.p. injection of CDP or treated with CDP alone. Tumor size was measured three times per week, and volume was calculated as described in the “Methods” section. The histograms represent mean +/− 95% confidence intervals of tumor weight.

Mentions: Results showed that, as expected, CDP alone induced a significant inhibition of tumor growth, but also that ESOM pre-treatment induced a complete inhibition of tumor growth, with no evidence of the tumor at the end of the experiments (Figure 2). Supporting previous results obtained with human cell lines of different histotypes [3], ESOM alone, at this dosage and with this schedule of treatment did not induce significant inhibition of tumor growth (not shown). This set of experiments further supported the potential use of PPI in improving the effectiveness of chemotherapy in osteosarcoma patients.


Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients' bed.

Ferrari S, Perut F, Fagioli F, Brach Del Prever A, Meazza C, Parafioriti A, Picci P, Gambarotti M, Avnet S, Baldini N, Fais S - J Transl Med (2013)

In vivo effects of ESOM on tumor growth in CB.17 SCID/SCID mice. Mice were engrafted with Saos-2 cells via s.c. injection in the right flank. At the time of tumor appearance (approximately 7–10 days after injection), mice were left untreated or were pre-treated with 25 mg/kg of ESOM 24 hrs before the i.p. injection of CDP or treated with CDP alone. Tumor size was measured three times per week, and volume was calculated as described in the “Methods” section. The histograms represent mean +/− 95% confidence intervals of tumor weight.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815282&req=5

Figure 2: In vivo effects of ESOM on tumor growth in CB.17 SCID/SCID mice. Mice were engrafted with Saos-2 cells via s.c. injection in the right flank. At the time of tumor appearance (approximately 7–10 days after injection), mice were left untreated or were pre-treated with 25 mg/kg of ESOM 24 hrs before the i.p. injection of CDP or treated with CDP alone. Tumor size was measured three times per week, and volume was calculated as described in the “Methods” section. The histograms represent mean +/− 95% confidence intervals of tumor weight.
Mentions: Results showed that, as expected, CDP alone induced a significant inhibition of tumor growth, but also that ESOM pre-treatment induced a complete inhibition of tumor growth, with no evidence of the tumor at the end of the experiments (Figure 2). Supporting previous results obtained with human cell lines of different histotypes [3], ESOM alone, at this dosage and with this schedule of treatment did not induce significant inhibition of tumor growth (not shown). This set of experiments further supported the potential use of PPI in improving the effectiveness of chemotherapy in osteosarcoma patients.

Bottom Line: Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness.An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors.Notably, no significant increase in toxicity was recorded in PPI treated patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Anti-Tumour Drugs Section Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy. stefano.fais@iss.it.

ABSTRACT

Background: Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H +-rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma.

Method: MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin.

Results: Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients.

Conclusion: This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy.

Show MeSH
Related in: MedlinePlus