Lansoprazole as a rescue agent in chemoresistant tumors: a phase I/II study in companion animals with spontaneously occurring tumors.
BACKGROUND
The 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.


METHODS
Thirty-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.


RESULTS
The 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.


CONCLUSIONS
high 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.
SAFU Department, Regina Elena Cancer Institute, Rome, Italy.
Enrico P
EP
Spugnini
Alfonso
A
Baldi
Sabrina
S
Buglioni
Francesca
F
Carocci
Giulia Milesi
GM
de Bazzichini
Gianluca
G
Betti
Ilaria
I
Pantaleo
Francesco
F
Menicagli
Gennaro
G
Citro
Stefano
S
Fais
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002415:Cats; D057176:Compassionate Use Trials; D004285:Dogs; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D064747:Lansoprazole; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000662:veterinary*; D016896:Treatment Outcome
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000970:Antineoplastic Agents; D064747:Lansoprazole