Adenosine Articles 3 - Cancer

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

            (Agteresch, Leij-Halfwerk et al. 2000) Download

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 inverted question mark6, 6-(2)H(2)glucose and inverted question mark3-(13)Calanine. 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 inverted question markbaseline, 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.


Pharmacokinetics of intravenous ATP in cancer patients

            (Agteresch, Dagnelie et al. 2000) Download

OBJECTIVE: To characterise the pharmacokinetics of adenosine 5'-triphosphate (ATP) in patients with lung cancer after i.v. administration of different ATP dosages. METHODS: Twenty-eight patients received a total of 176 i.v. ATP courses of 30 h. Fifty-two infusions were given as low-dose infusions of 25-40 microg kg(-1) min(-1), 47 as middle-dose infusions of 45-60 microg kg(-1) min(-1) and 77 as high-dose infusions of 65-75 microg kg(-1) min(-1) ATP. Kinetic data of ATP concentrations in erythrocytes were available from 124 ATP courses. Results are expressed as mean +/- SEM. RESULTS: Most ATP courses in cancer patients were without side effects (64%), and side effects occurring in the remaining courses were mild and transient, resolving within minutes after decreasing the infusion rate. Baseline ATP concentration in erythrocytes was 1,554 +/- 51 micromol l(-1). ATP plateau levels at 24 h were significantly increased by 53 +/- 3, 56 +/- 3 and 69 +/- 2% after low-dose, middle-dose and high-dose ATP infusions, respectively. At the same time, significant increases in plasma uric acid concentrations were observed: 0.06 +/- 0.01, 0.11 +/- 0.01 and 0.16 +/- 0.01 mmol l(-1), respectively. The mean half-time for disappearance of ATP from erythrocytes, measured in five patients, was 5.9 +/- 0.5 h. CONCLUSIONS: During constant i.v. infusion of ATP in lung cancer patients, ATP is taken up by erythrocytes and reaches dose-dependent plateau levels 50-70% above basal concentrations at approximately 24 h.

Beneficial effects of adenosine triphosphate on nutritional status in advanced lung cancer patients: a randomized clinical trial

            (Agteresch, Rietveld et al. 2002) Download

PURPOSE: In a randomized clinical trial in patients with advanced non-small-cell lung cancer (NSCLC), infusion with adenosine 5'-triphosphate (ATP) inhibited loss of body weight and quality of life. In the present article, the effects of ATP on body composition, energy intake, and energy expenditure as secondary outcome measures in the same patients are reported. PATIENTS AND METHODS: Patients with NSCLC, stage IIIB or IV, were randomized to receive either 10 intravenous, 30-hour ATP infusions every 2 to 4 weeks or no ATP. Fat mass (FM), fat-free mass (FFM), and arm muscle area were assessed at 4-week intervals for 28 weeks. Food intake, body cell mass (BCM), and resting energy expenditure (REE) were assessed at 8-week intervals for 16 weeks. Between-group differences were tested for statistical significance by repeated-measures analysis of covariance. RESULTS: Fifty-eight patients were randomized (28 ATP, 30 control). No change in body composition over the 28-week follow-up period was found in the ATP group, whereas, per 4 weeks, the control group lost 0.6 kg of FM (P =.004), 0.5 kg of FFM (P =.02), 1.8% of arm muscle area (P =.02), and 0.6% of BCM/kg body weight (P =.054) and decreased 568 KJ/d in energy intake (P =.0001). Appetite also remained stable in the ATP group but decreased significantly in the control group (P =.0004). No significant differences in REE between the ATP and control groups were observed. CONCLUSION: The inhibition of weight loss by ATP infusions in patients with advanced NSCLC is attributed to counteracting the loss of both metabolically active and inactive tissues. These effects are partly ascribed to maintenance of energy intake.

Intravenous ATP infusions can be safely administered in the home setting: a study in pre-terminal cancer patients

            (Beijer, Gielisse et al. 2007) Download

The aim of the study was to investigate the safety of adenosine 5'-triphosphate (ATP) administration at home in pre-terminal cancer patients. Included were patients with cancer for whom medical treatment options were restricted to supportive care, who had a life expectancy of less than 6 months, a World Health Organization performance status 1 or 2, and suffered from at least one of the following complaints: fatigue, anorexia or weight loss >5% over the previous 6 months. Side effects were registered systematically on a standard form according to the National Cancer Institute (NCI) Common Toxicity Criteria. Fifty-one patients received a total of 266 intravenous ATP infusions. Of these, 11 infusions (4%) were given at the lowest dose of 20 microg kg(-1) min(-1), 85 infusions (32%) at 25-40 microg kg(-1) min(-1), and 170 (64%) at the highest dose of 45-50 microg kg(-1) min(-1) ATP. The majority of ATP infusions (63%) were without side effects. Dyspnea was the most common side effect (14% of infusions), followed by chest discomfort (12%) and the urge to take a deep breath (11%). No symptoms of cardiac ischemia occurred in any of the infusions. All side effects were transient and resolved within minutes after lowering the ATP infusion rate. Side effects were most frequent in the presence of cardiac disorders. We conclude that ATP at a maximum dose of 50 microg kg(-1) min(-1) can be safely administered in the home setting in patients with pre-terminal cancer.

Application of adenosine 5'-triphosphate (ATP) infusions in palliative home care: design of a randomized clinical trial

            (Beijer, van Rossum et al. 2007) Download

BACKGROUND: Palliative care in cancer aims at alleviating the suffering of patients. A previous study in patients with advanced non-small-cell lung cancer showed that adenosine 5'-triphosphate (ATP) infusions had a favourable effect on fatigue, appetite, body weight, muscle strength, functional status and quality of life. The present study was designed 1. To evaluate whether ATP has favourable effects in terminally ill cancer patients, 2. To evaluate whether ATP infusions may reduce family caregiver burden and reduce the use of professional health care services, and 3. To test the feasibility of application of ATP infusions in a home care setting. METHODS/DESIGN: The study can be characterized as an open-labelled randomized controlled trial with two parallel groups. The intervention group received usual palliative care, two visits by an experienced dietician for advice, and regular ATP infusions over a period of 8 weeks. The control group received palliative care as usual and dietetic advice, but no ATP. This paper gives a description of the study design, selection of patients, interventions and outcome measures. DISCUSSION: From April 2002 through October 2006, a total of 100 patients have been randomized. Follow-up of patients will be completed in December 2006. At the time of writing, five patients are still in follow up. Of the 95 patients who have completed the study, 69 (73%) have completed four weeks of follow-up, and 53 (56%) have completed the full eight-week study period. The first results are expected in 2007.

Phase II study of intravenous adenosine 5'-triphosphate in patients with previously untreated stage IIIB and stage IV non-small cell lung cancer

            (Haskell, Mendoza et al. 1998) Download

Fifteen patients with Stage IIIB or IV non-small cell lung cancer gave informed consent to receive three or more 96-hour infusions of ATP at a dose of 50 mcg/kg/min or higher to determine whether ATP has antineoplastic activity against this tumor type and to better define the spectrum of toxicity for ATP given as a single agent. There were no objective complete or partial responses observed. The median survival of the overall group was 187 days and the median time to tumor progression was 113 days. The major toxic side effects were chest pain and dyspnea, leading to the cessation of treatment in 5 patients. We conclude that ATP at this dose and schedule of administration is an inactive agent in patients with advanced non-small cell lung cancer.

Adenosine triphosphate: does it help cancer patients "get bigger and stronger"?

            (Jatoi and Loprinzi 2002) Download


References

Agteresch, H. J., P. C. Dagnelie, et al. (2000). "Pharmacokinetics of intravenous ATP in cancer patients." Eur J Clin Pharmacol 56(1): 49-55.

Agteresch, H. J., S. Leij-Halfwerk, et al. (2000). "Effects of ATP infusion on glucose turnover and gluconeogenesis in patients with advanced non-small-cell lung cancer." Clin Sci (Lond) 98(6): 689-95.

Agteresch, H. J., T. Rietveld, et al. (2002). "Beneficial effects of adenosine triphosphate on nutritional status in advanced lung cancer patients: a randomized clinical trial." J Clin Oncol 20(2): 371-8.

Beijer, S., E. A. Gielisse, et al. (2007). "Intravenous ATP infusions can be safely administered in the home setting: a study in pre-terminal cancer patients." Invest New Drugs 25(6): 571-9.

Beijer, S., E. van Rossum, et al. (2007). "Application of adenosine 5'-triphosphate (ATP) infusions in palliative home care: design of a randomized clinical trial." BMC Public Health 7: 4.

Haskell, C. M., E. Mendoza, et al. (1998). "Phase II study of intravenous adenosine 5'-triphosphate in patients with previously untreated stage IIIB and stage IV non-small cell lung cancer." Invest New Drugs 16(1): 81-5.

Jatoi, A. and C. L. Loprinzi (2002). "Adenosine triphosphate: does it help cancer patients "get bigger and stronger"?" J Clin Oncol 20(2): 362-3.