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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

Incidence of GR in eligible patients (PPI-Osteosarcoma) versus the comparator group (ISG/OS-1). Comparison among the groups by means of Fisher’s exact test: Osteoblastic p = 0.32, Fibroblastic + Telangectatic 0.70, Chondroblastic p = 0.07.
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Figure 3: Incidence of GR in eligible patients (PPI-Osteosarcoma) versus the comparator group (ISG/OS-1). Comparison among the groups by means of Fisher’s exact test: Osteoblastic p = 0.32, Fibroblastic + Telangectatic 0.70, Chondroblastic p = 0.07.

Mentions: A resection was performed in 93 patients, whereas 5 patients underwent amputation. The surgical margins evaluation was available in 93 patients. In 9 patients the surgical margins were classified as marginal (8 patients) or wide but contaminated (3 patients), the remaining patients had wide or radical surgical margins. On histology, a GR was detected in 56 (57%) patients (Figure 3). According to the histological histotype the highest rate of GR was seen in patients with the chondroblastic histotype followed by those with telangiectatic, fibroblastic, and osteoblastic variants (Figure 3). In the comparator group (ISG/OS-1), the incidence of GR was 47%, close to that observed in the investigational group (Figure 3). According to the histotype, a similar percentage of good response was observed in osteoblastic and in the pool of fibroblastic and telangiectatic osteosarcoma whereas in patients with chondroblastic osteosarcoma the incidence of GR was only 25%, a remarkably lower rate as compared to the 61% recorded in the group of patients pre-treated with ESOM.


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)

Incidence of GR in eligible patients (PPI-Osteosarcoma) versus the comparator group (ISG/OS-1). Comparison among the groups by means of Fisher’s exact test: Osteoblastic p = 0.32, Fibroblastic + Telangectatic 0.70, Chondroblastic p = 0.07.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Incidence of GR in eligible patients (PPI-Osteosarcoma) versus the comparator group (ISG/OS-1). Comparison among the groups by means of Fisher’s exact test: Osteoblastic p = 0.32, Fibroblastic + Telangectatic 0.70, Chondroblastic p = 0.07.
Mentions: A resection was performed in 93 patients, whereas 5 patients underwent amputation. The surgical margins evaluation was available in 93 patients. In 9 patients the surgical margins were classified as marginal (8 patients) or wide but contaminated (3 patients), the remaining patients had wide or radical surgical margins. On histology, a GR was detected in 56 (57%) patients (Figure 3). According to the histological histotype the highest rate of GR was seen in patients with the chondroblastic histotype followed by those with telangiectatic, fibroblastic, and osteoblastic variants (Figure 3). In the comparator group (ISG/OS-1), the incidence of GR was 47%, close to that observed in the investigational group (Figure 3). According to the histotype, a similar percentage of good response was observed in osteoblastic and in the pool of fibroblastic and telangiectatic osteosarcoma whereas in patients with chondroblastic osteosarcoma the incidence of GR was only 25%, a remarkably lower rate as compared to the 61% recorded in the group of patients pre-treated with ESOM.

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