Effect of hyperthermiain vitro andin vivo on adenine and pyridine nucleotide pools in human peripheral lymphocytes

Abstract

Hyperthermia has been shown in vitro and in vivo to potentiate the effects of ionizing irradiation. Previous studies found that hyperthermia alters the metabolism of adenosine diphosphate (ADP)-ribose polymers required for recovery from DNA damage and that poly(ADP-ribose) polymerase activity is very sensitive to cellular nicotinamide-adenine dinucleotide (NAD) levels. Thus, the effect of 41.8"C hyperthermia in vitro and in vivo on NAD and adenosine triphosphate (ATP) levels was studied in human peripheral lymphocytes. In vifro studies showed significant decreases in oxidized NAD (NAD') and ATP levels after heating that simulated a clinical whole-body hyperthermia (WBH) treatment. This nucleotide depletion could not be attributed to nucleotide leakage or increased enzymatic NAD+ consumption. As the reduction of NAD observed was sufficient to decrease poly(ADP4bose)polymerase activity by 5070, the studies were extended to clinical cases. Cellular NAD+ and ATP were measured in previously stored lymphocytes obtained from four patients before and after WBH; a statistically significant decrease in NAD+ was observed after WBH which quantitatively agreed with the in vitro results. Based on these results a prospective study was done in three patients: NAD+ was extracted immediately on sample collection, and the kinetics of WBH-induced NAD depletion were studied. These data, which agree quantitatively with the laboratory results, are presented. Cancer 67:2096-2102,1991. RECLINICAL STUDIES show the potential of temper-P atures as high as 42°C to enhance the effects of ionizing irradiation, chemotherapy, and immunotherapy.'-6 The results of such laboratory work have been extrapolated to the clinical sphere, with promising, but not de

Fatigue associated with cancer and its treatment

“…Compromised blood supply to tumors results in oxygen-depleted areas of the tumors, associated with deprivation of nutrients and energy and a hostile metabolic microenvironment (i.e. severe tissue acidosis), including decreased ATP in tumor cells [66], and lymphocytes [107]. Incubation of malignant cell lines with cytostatic drugs has resulted in marked decreases in intracellular ATP levels, the degree of decrease varying with the strength of the cytostatic drugs [72].…”

Modulation of VP-16 cytotoxicity by carboplatin and 41.8°C hyperthermia

“…Cellular NAD + functions as the substrate for the DNA-repair enzyme PARP (Berger 1985). We postulate that the elevation in NAD + results from alterations in NAD + metabolism that occur following DNA damage which may include: (i) increased NAD + consumption by ADP-ribose transfer reactions and a subsequent stimulation of NAD + biosynthesis (Berger 1985); (ii) decreased NAD + biosynthesis secondary to hyperthermia, which in combination with carboplatin lowers NAD + suciently to activate biosynthesis (Robins et al 1991); and (iii) hyperthermiainduced inhibition of poly(ADP-ribose) glycohydrolase resulting in decreased PARP activity due to decreased turnover of polymers on the automodi®ed polymerase (Jonsson et al 1988).…”

“…Platinum agents, e.g., carboplatin, represent a class of drugs that can aect cellular nucleotide pools (Robins et al 1991). Carboplatin induces DNA strand breaks resulting in the activation of PARP.…”

“…Upon activation, this enzyme utilizes NAD + as a substrate to synthesize homopolymers of ADP-ribose that covalently modify PARP, other acceptor proteins including histones, nuclear matrix proteins (Cardenas-Corona et al 1987), and topo II (Masahiko and Lindahl 1992). Hyperthermia also alters cellular NAD + by inhibiting nucleotide biosynthesis (Robins et al 1991). Furthermore, hyperthermia has been shown to alter ADP-ribose polymer metabolism (Jonsson et al 1988) by inhibiting the degrading enzyme, poly(ADP-ribose) glycohydrolase (Jonsson et al 1988).…”

Hyperthermia and mafosfamide in a human-derived malignant pleural mesothelioma cell line

“…An important factor is the inhibition of intracellular repair mechanisms (due to synthesis of NAD+) during hyperthermia (Robins et al 1991). We studied the effects of hyperthermia (41.7°C for 1 h) combined with different dosages of mafosfamide and by examining the morphology and growth patterns of the human malignant pleural mesothelioma cell line MSTO-211H.…”