Effects of ATP infusion on glucose turnover and gluconeogenesis in patients with advanced non-small-cell lung cancer

Abstract

Cancer cachexia is associated with elevated lipolysis, proteolysis and gluconeogenesis. ATP infusion has been found to significantly inhibit loss of body weight, fat mass and fat-free mass in patients with advanced lung cancer. The present study was aimed at exploring the effects of ATP on whole-body glucose turnover, alanine turnover and gluconeogenesis from alanine. Twelve patients with advanced non-small-cell lung cancer (NSCLC) were studied 1 week before and during 22-24 h of continuous ATP infusion. After an overnight fast, turnover rates of glucose and alanine, and gluconeogenesis from alanine, were determined using primed constant infusions of ¿6, 6-(2)H(2)ğlucose and ¿3-(13)Călanine. Thirteen NSCLC patients and eleven healthy subjects were studied as control groups without ATP infusion. During high-dose ATP infusion (75 microg.min(-1).kg(-1)), glucose turnover was 0.62+/-0.07 mmol.h(-1).kg(-1), compared with 0. 44+/-0.13 mmol.h(-1).kg(-1) at baseline (P=0.04). For gluconeogenesis a similar, but non-significant, trend was observed ¿baseline, 0.30+/-0.16 mmol.h(-1).kg(-1); during ATP, 0.37+/-0.13 mmol.h(-1).kg(-1) (P=0.08). At lower ATP doses (37-50 microg. min(-1).kg(-1)) these effects were not detected. The relative increase in glucose turnover during ATP infusion compared with baseline showed a significant correlation with the ATP dose (r=0.58, P=0.02). No change in alanine turnover was observed at any ATP dose. The results of this study indicate an increase in glucose turnover during high-dose ATP infusion compared with baseline levels. During high-dose ATP infusion, glucose turnover was similar to that during low-dose ATP infusion and to that in control NSCLC patients. Between ATP infusions, however, glucose turnover in patients treated with high-dose ATP was significantly lower than that in the low-dose and control NSCLC patients (P=0.04 and P=0.03 respectively), and similar to that in healthy subjects. This would suggest that repeated high-dose ATP infusions may inhibit glucose turnover between infusion periods.

Oral bioavailability of ATP after prolonged administration

“…shows that plasma ATP concentrations after administration of 5000 mg ATP on days 0 and 28 did not differ significantly between the different dosage groups (P¼0•42 for day 0 and P¼0•47 for day28), nor between days 0 and 28 (P. 0•05).…”

Hepatic 31P magnetic resonance spectroscopy: a hepatologist's user guide

“…Intriguing work by Leij‐Halfwerk, et al (44) is elucidating the pathophysiology of decreased hepatic energy and phosphorylation status in weight losing non‐small cell lung cancer patients. These investigators have used intravenous alanine to evaluate hepatic energy generating capacity during a gluconeogenic challenge, and have suggested ATP infusion to correct hepatic energy deficits (45, 46). It is noteworthy that 31 P MRS is uniquely suited to such research because it can non‐invasively measure in vivo biochemical processes and thus allows researches to study dynamic responses to physiologic challenges (e.g.…”

Extracellular ATP and Cancer—An Overview with Special Reference to P2 Purinergic Receptors

“…Phase II and III studies, however, produced more controversial results. Whereas one trial concluded that intravenous ATP was an inactive agent and caused no objective complete or partial responses [52], another group reported to have proved that ATP had beneficial effects on weight, muscle strength, and quality of life in patients with advanced non-small-cell lung cancer [53], partly due to altering glucose turnover and gluconeogenesis [54] and increasing liver energy status [55]. Nevertheless, even this group found that the ten intravenous 30-h ATP infusions every 2-4 weeks over a 24-week period they applied did not lead to tumour regression, and although the treatment resulted in prolonged survival of the subgroup of weightlosing stage IIIB patients, this was not seen in the case of stage IV or weight-stable patients [56].…”