Abstract
BackgroundThe treatment of human cancer has been seriously hampered for decades by resistance to chemotherapeutic drugs. Mechanisms underlying this resistance are far from being entirely known. A very efficient mechanism of tumor resistance to drugs is related to the modification of tumour microenvironment through changes in the extracellular and intracellular pH. The acidification of tumor microenvironment depends on proton pumps that actively pump protons outside the cells, mostly to avoid intracellular acidification. In fact, we have shown in pre-clinical settings as pre-treatment with proton-pumps inhibitors (PPI) increase tumor cell and tumor responsiveness to chemotherapeutics. In this study pet with spontaneously occurring cancer proven refractory to conventional chemotherapy have been recruited in a compassionate study.MethodsThirty-four companion animals (27 dogs and 7 cats) were treated adding to their chemotherapy protocols the pump inhibitor lansoprazole at high dose, as suggested by pre-clinical experiments. Their responses have been compared to those of seventeen pets (10 dogs and 7 cats) whose owners did not pursue any other therapy than continuing the currently ongoing chemotherapy protocols.ResultsThe drug was overall well tolerated, with only four dogs experiencing side effects due to gastric hypochlorhydria consisting with vomiting and or diarrhea. In terms of overall response twenty-three pets out of 34 had partial or complete responses (67.6%) the remaining patients experienced no response or progressive disease however most owners reported improved quality of life in most of the non responders. On the other hand, only three animals in the control group (17%) experienced short lived partial responses (1-3 months duration) while all the others died of progressive disease within two months.Conclusionshigh dose proton pump inhibitors have been shown to induce reversal of tumor chemoresistance as well as improvement of the quality of life in pets with down staged cancer and in the majority of the treated animals PPI were well tolerated. 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, progression, and invasion occur in a complex and dynamic microenvironment which depends on the hosts and sites where tumors develop
Dogs pumps inhibitors (PPI) COHORT: Twenty-seven dogs entered the study over a 19 months period and their characteristics and treatment protocols are summarized in tables 4, 5 and 6
We have showed a dramatic decrease of pain in dogs with osteosarcoma and in cats affected by oral squamous cell carcinoma invading the maxilla or the mandible, following clinical response to the treatment with lansoprazole
Summary
Progression, and invasion occur in a complex and dynamic microenvironment which depends on the hosts and sites where tumors develop. Tumor cells rely on H+ exchangers to relieve themselves from the dangerous protons byproduct of cancer metabolism that could trigger a cascade of lytic enzymes that would lead to self-digestion Among these the most prominent are the vacuolar H+-ATPases (VATPases). The acidic tumor environment is a consequence of anaerobic glucose metabolism resulting in accumulation of acid byproducts such as lactates This involves the upregulation of hypoxia-inducible factor 1a [15] or can be dependent on inadequate tumor perfusion, hypoxia secondary to disordered tumor growth or enhanced transmembrane pH regulation [16]. In this study pet with spontaneously occurring cancer proven refractory to conventional chemotherapy have been recruited in a compassionate study
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