In fact, 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. This depends on the concentration of cytostatics accumulated within the cells, phenomenon that is dependent on functional expression of efflux transporters, but also on the pH of extracellular microenvironment. The other factor to be taken into account when planning a treatment procotol, is the response to chemotherapy by tumor cells. Several studies in human and veterinary oncology have shown efficacy of low dose alkylating agents such as cyclophosphamide and chlorambucil to directly approach refractory cancers or as adjuvant therapy for highly metastatic or metastasizing tumor. Metronomic chemotherapy is not only almost devoid of toxic effects, but also exerts e direct citotoxicity combined with an antiangiogenic activity resulting in significant efficacy. A new therapeutic paradigm has recently been devised, consisting of the use of low-dose chemotherapeutics at short intervals (so-called, metronomic chemotherapy), in the absence of extended drug-free periods. As a consequence, despite the discovery of a significant number of these drugs and the huge number of clinical trials that have been undertaken to develop novel multi-drugs protocols, results has been modest in terms of cure or life extension of cancer patients, especially those with advanced-stage or metastatic disease. These interruptions, however, also permit cancer cells to become resistant to chemotherapy and hence to promote a disease recurrence.
Wahl model 9966 full#
As a consequence of this approach, patients must go through long periods off therapy, allowing for their full recovery from the adverse effects of chemotherapy. In the attempt to maximize their efficacy, they are administered at a maximal tolerated dose (MTD), the highest amount of the drug associated with tolerable toxicity and manageable side effects. Standard anticancer drugs were devised accordingly to Erlich’s magic bullet concept and rely on their capacity to directly kill malignant cells. Further studies are warranted to assess the efficacy of this strategy in patients with advanced cancers in companion animals as well as in humans.Ĭancer initiation, invasion and dissemination are dynamic phenomena influenced by tumor microenvironment and host factors. Patient 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. Median time to terminal event was 34 weeks for the experimental group versus 2 weeks in the controls (p= 0.042). On the other hand, only one patient in the control group experienced a complete response (10%) and three other experienced short lived responses. 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. The protocol was overall well tolerated, with only two dogs experiencing side effects due to gastric hypochlorhydria consisting with vomiting and or diarrhea. Their responses have been evaluated by clinical and instrumental evaluation and matched to those of the control group.
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. Single arm, non randomized phase II open study, with historical control group, evaluating safety and efficacy of the combination of metronomic chemotherapy and alkalization. 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.
Moreover, we have shown in veterinary clinical settings that pre-treatment with proton-pumps inhibitors (PPI) increases tumor responsiveness to chemotherapeutics. Metronomic chemotherapy has shown efficacy in adjuvant fashion as well as in the treatment of pets with advanced disease. A very efficient mechanism of tumor resistance to drugs is the proton pumps-mediated acidification of tumor microenvironment. The treatment of human cancer has been seriously hampered for decades by resistance to chemotherapeutic drugs.
0 kommentar(er)
