Improved Chemotherapy Outcomes of Patients With Small-cell Lung Cancer Treated With Combined Alkalization Therapy and Intravenous Vitamin C – Cancer Diagnosis & Prognosis

+/H⁺ exchangers and monocarboxylate transporters, and protons resulting from the production of lactic acid during glycolysis are exported from cancer cells, resulting in a decrease in extracellular pH and an increase in intracellular pHnHighlight:Firstly, in patients with advanced-stage epidermal growth factor receptor mutation-positive nonSCLC, prolonged progression-free survival (19.5 months) was achieved by a regimen of low-dose epidermal growth factor receptor tyrosine kinase inhibitor (56%±22% of the standard dosage) and an alkaline diet (eating fruit and vegetables and limiting meat and milk)nHighlight:We also reported that an alkaline diet increased the urine pHnHighlight:Secondly, in a retrospective study of patients with advanced pancreatic cancer undergoing alkalization therapy, a prolonged median overall survival (OS) was observed in patients with a urine pH of more than 7.0 compared with those with a urine pH of 7.0 or lessnHighlight:dehydroascorbate (DHA), which is the oxidized form of vitamin C, inhibits glyceraldehyde 3-phosphate dehydrogenase and leads to anticancer effectsnHighlight:suppression of inflammationnHighlight:investigate the effects of the combination of alkalization therapy and intravenous vitamin C treatment on chemotherapy outcomes in patients with SCLCnHighlight:retrospectivelynHighlight:Karasuma Wada ClinicnHighlight:Alkalization therapy was defined as a combination of an alkaline diet and bicarbonate therapynHighlight:alkaline diet was meals comprising a large amount of vegetables and fruit, and minimal meat and dairy productsnHighlight:at least 400 g of fruit and vegetables a day and not to take any meat and dairy productsnHighlight:Patients who received alkalization therapy also received oral bicarbonate (3.0−5.0 g/day)nHighlight:Patients who agreed to receive vitamin C treatment were given vitamin C (25-50 g/day by infusion every 1 or 2 weeks)nHighlight:The mean urine pH of the intervention group was significantly higher than that of the control groupnHighlight:The median OS from the time of diagnosis for the intervention group was 44.2 months (n=12, 95% confidence interval=22.0−not reached) as compared with 17.7 months for patients in the control groupnHighlight:In the present retrospective study, we demonstrated that the median OS of patients with SCLC who received a combination of alkalization therapy and intravenous vitamin C treatment together with chemotherapy was significantly longer than that of those who received only chemotherapynHighlight:The combination of alkalization therapy and intravenous vitamin C treatment may exert synergetic effects that contribute to the favorable outcomes of patients with SCLC, because the median OS was not prolonged in those who received only alkalization therapy or only intravenous vitamin C treatment together with chemotherapynHighlight:a significant increase in mean urine pH was observed in patients who received alkalization therapy and intravenous vitamin C treatment compared with the control group in the present studynHighlight:meat and dairy products have an acidifying effect on urine pHnHighlight:fruit and vegetables have an alkalizing effectnHighlight:A clinical study has shown the safety and tolerability of the long-term consumption of bicarbonate (0.5 g/kg/day, i.e., 25 g/50 kg body weight), and bicarbonate is also known to have buffering effects and to increase urine pH levelsnHighlight:We believe empirically that without alkalization therapy, chemotherapy with vitamin C does not affect urine pH;nHighlight:Although the association between the pH of the tumor microenvironment and urine pH was not clarified in this study, computer simulation studies reported that bicarbonate consumption leads to an increase in the pH of the tumor microenvironmentnHighlight:in vivo study demonstrated that bicarbonate administration in mouse models of metastatic breast cancer increased the pH of tumor cells and resulted in the suppression of cancer progressionnHighlight:Neutralization of the acidic pH of the extracellular tumor microenvironment has been shown to lead to improvements in multi-chemotherapeutic drug resistance in several in vivo and in vitro studiesnHighlight:acidic environment, weak-base chemotherapeutic drugs are positively charged and become trapped in extracellular compartments, leading to a reduction in their cellular uptake and efficacynHighlight:acidic tumor microenvironment is also associated with the mechanisms of multidrug effluxnHighlight:P-glycoprotein, which is a multidrug transporter, is activated and expressed in an acidic environment, and results in a decrease in the level of chemotherapeutic drugs in the bodynHighlight:increase in the number of exosomes is observed in an acidic tumor microenvironment, which assist in removing chemotherapeutic drugs from cancer cellsnHighlight:a prolonged median OS and increased urine pH was observed in patients in the intervention group compared with those in the control groupnHighlight:urine pH of higher than 7.0, or a urine ΔpH of more than 1.0 was significantly associated with prolonged OS in patients with advanced pancreatic cancer compared with a urine pH of 7.0 or lower, or a urine ΔpH of 1.0 or lessnHighlight:In this study, a prolonged median OS was observed in patients with SCLC who received both alkalization therapy and intravenous vitamin C treatment together with chemotherapy, compared with those who received only chemotherapynHighlight:About 90% or more patients with SCLC have somatic mutations in the tumor suppressor gene TP53 which are associated with the overexpression of mutant P53 protein in tumor cells (35). The P53 protein binds to glucose-6-phosphate dehydrogenase, which is the first and rate-limiting enzyme of the pentose phosphate pathway and suppresses the overactivation of glycolysis. On the other hand, mutant P53 proteins lack this glucose-6-phosphate dehydrogenase-inhibitory activity, which may result in activated glycolysis via the pentose phosphate pathwaynHighlight:Vitamin C is transported into cancer cells via the glucose transporter, is oxidized to DHA, and then DHA inhibits glyceraldehyde 3-phosphate dehydrogenase, which may result in the suppression of activated glycolysis, particularly in cancer cells with high glycolytic metabolismnHighlight:methods to measure the pH of the tumor microenvironment, such as acido-chemical exchange saturation transfer magnetic resonance imaging, which can measure the extracellular pH of the tumor microenvironment using the ratio of two pH-dependent signals from such imaging may be useful for clarifying the association between the combination of alkalization therapy plus intravenous vitamin C treatment and pH changes of the tumor microenvironmentn]]>