Abstract
BackgroundThe treatment of human cancer has been seriously hampered for decades by resistance to chemotherapeutic drugs. A very efficient mechanism of tumor resistance to drugs is the proton pumps-mediated acidification of tumor microenvironment. Metronomic chemotherapy has shown efficacy in adjuvant fashion as well as in the treatment of pets with advanced disease. Moreover, we have shown in veterinary clinical settings that pre-treatment with proton-pumps inhibitors (PPI) increases tumor responsiveness to chemotherapeutics. In this study pet with spontaneously occurring cancer have been recruited to be treated by a combination of metronomic chemotherapy and high dose PPIs and their responses have been matched to those of a historical control of ten patients treated with metronomic chemotherapy alone.MethodsSingle arm, non randomized phase II open study, with historical control group, evaluating safety and efficacy of the combination of metronomic chemotherapy and alkalization. Twenty-four companion animals (22 dogs and 2 cats) were treated adding to their metronomic chemotherapy protocol the pump inhibitor lansoprazole at high dose, and a water alkalizer. Their responses have been evaluated by clinical and instrumental evaluation and matched to those of the control group.ResultsThe protocol was overall well tolerated, with only two dogs experiencing side effects due to gastric hypochlorhydria consisting with vomiting and or diarrhea. In terms of overall response, in the alkalized cohort, 18 out of 24 had partial or complete responses (75%), two patients had a stable disease and the remaining patients experienced no response or progressive disease. On the other hand, only one patient in the control group experienced a complete response (10%) and three other experienced short lived responses. Median time to terminal event was 34 weeks for the experimental group versus 2 weeks in the controls (p= 0.042).ConclusionsPatient alkalization has shown to be well tolerated and to increase tumor response to metronomic chemotherapy as well the quality of life in pets with advanced cancer. Further studies are warranted to assess the efficacy of this strategy in patients with advanced cancers in companion animals as well as in humans.
Highlights
Cancer initiation, invasion and dissemination are dynamic phenomena influenced by tumor microenvironment and host factors
The acidity of tumor microenvironment is a key factor in the low level of responsiveness of tumor cells to chemotherapeutics, and proton exchangers have a crucial impact in extracellular acidification of cancer cells [18,19]
A role of nanovesicles released by resistant cancer cells has been in elimination of tumor drug such as cisplatin, and extracellular acidity and exosomes release belong to a framework exerting a central role of malignant cancer unresponsiveness to chemotherapy [25]
Summary
Invasion and dissemination are dynamic phenomena influenced by tumor microenvironment and host factors. The acidic tumor environment is a consequence of anaerobic glucose metabolism resulting in accumulation of acids such as lactates, leading to enhanced transmembrane pH regulation [22] These proton pumps, together with other ion exchangers, play a crucial function in the establishment and maintenance of cancer microenvironment and their action results in the selection of more aggressive cell phenotypes able to survive in this highly hostile microenvironment, with a key role in the establishment and maintenance of chemoresistance [19]. The aim of this study was to investigate the feasibility, tolerability and efficacy of high dose proton pump inhibitor lansoprazole combined with water alkalization within a metronomic protocol in companion animals affected by advanced or highly metastatic neoplasms. In this study pet with spontaneously occurring cancer have been recruited to be treated by a combination of metronomic chemotherapy and high dose PPIs and their responses have been matched to those of a historical control of ten patients treated with metronomic chemotherapy alone
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