Lymphocyte dysfunction caused by deficiencies in purine metabolism

Carson, Dennis A.; Lakow, Ellen; Wasson, D B; Kamatani, Naoyuki

doi:10.1016/0167-5699(81)90010-4

Cited by 29 publications

(13 citation statements)

References 17 publications

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“…5). In agreement with earlier results, ATP levels decreased significantly after 24 h exposure to the two deoxynucleosides (15,19). Table II summarizes the time course of the effects of deoxyadenosine on ADA inhibited resting human peripheral blood lymphocytes.…”

Section: Introductionsupporting

confidence: 77%

“…Not The experiment was performed as described in Table I surprisingly, a severe fall in NAD pools is incompatible with the survival of resting or proliferating cells. The exquisite sensitivity of thymocytes and mature T lymphocytes to the noxious effects of deoxyadenosine is distinctive among human cell types (4,13,15). In general, the tendency of the cells to accumulate dATP explains their sensitivity to deoxyadenosine.…”

Section: Discussionmentioning

confidence: 99%

“…The dATP is an established inhibitor of mammalian ribonucleotide reductase, and hence of DNA synthesis (I 1, 12). However, micromolar concentrations of deoxyadenosine are also toxic to ADAinhibited human peripheral blood lymphocytes that are arrested in prolonged Go phase (13)(14)(15). The ADA-resistant deoxyadenosine congener 2-chlorodeoxyadenosine (CdA) is similarly cytotoxic to resting human T cells, and has immunosuppressive and anti-leukemic properties (16,17).…”

Section: Introductionmentioning

confidence: 99%

“…Deoxyadenosine has been reported to block RNA synthesis (18), to decrease ATP levels (15,19), and to foster an accumulation of strand breaks in DNA (20). The actual importance of these events in causing cell death is entirely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes.

Seto¹,

Carrera²,

Kubota³

et al. 1985

J. Clin. Invest.

345

142

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Deoxyadenosine has been implicated as the toxic metabolite causing profound lymphopenia in immunodeficient children with a genetic deficiency of adenosine deaminase (ADA), and in adults treated with the potent ADA inhibitor deoxycoformycin. However, the biochemical basis for deoxyadenosine toxicity toward lymphocytes remains controversial. The present experiments have examined in detail the sequential metabolic changes induced in nondividing human peripheral blood lymphocytes by incubation with deoxyadenosine plus deoxycoformycin, or with 2-chlorodeoxyadenosine (CdA), an ADA resistant deoxyadenosine congener with anti-leukemic and immunosuppressive properties. The lymphotoxic effect of deoxyadenosine and CdA required their phosphorylation, and was inhibited by deoxycytidine. As early as 4 h after exposure to the deoxynucleosides, strand breaks in lymphocyte DNA began to accumulate, and RNA synthesis decreased. These changes were followed by a significant fall in intracellular NAD levels at 8 h, a drop in ATP pools at 24 h, and cell death by 48 h. Incubation of the lymphocytes with 5 mM nicotinamide, a NAD precursor and an inhibitor of poly(ADP-ribose) synthetase, prevented NAD depletion. The nicotinamide treatment also rendered the lymphocytes highly resistant to deoxyadenosine and CdA toxicity, without altering dATP formation or the accumulation of DNA strand breaks. The poly(ADPribose) synthetase inhibitor 3-aminobenzamide exerted a similar although less potent effect. These results suggest that NAD depletion, probably triggered by poly(ADP-ribose) formation, is the principle cause of death in normal resting human lymphocytes exposed to deoxyadenosine plus deoxycoformycin, or to CdA.

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Section: Introductionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes.

Seto¹,

Carrera²,

Kubota³

et al. 1985

J. Clin. Invest.

345

142

View full text Add to dashboard Cite

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“…Further studies revealed accumulation of dATP in the erythrocytes of these patients and excretion of the normally-not-detectable deoxyadenosine in urine (reviewed in Fox and Kelley [1], Mitchell and Kelley, [10], Thompson and Seegmiller [11], Martin and Gelfand [12], Gelfand and Cohen [13], and Carson et al [14]). Adenosine is not excreted in abnormal amounts because it is phosphorylated to AMP by adenosine kinase, for which deoxyadenosine is a poor substrate, and then metabolized to IMP or ADP.…”

Section: A Denosine Deaminase (A Da) Deficiencymentioning

confidence: 97%

Adenosine and adenosine receptors in immune function. Minireview and meeting report

Gilbertsen¹

1987

Agents and Actions

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Biochemical consequences of 2′-deoxycoformycin treatment in a patient with T-cell lymphoma. Some unusual findings

Korte

Haverkort

Leeuwen

et al. 1987

Cancer

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The nucleotide content of the various blood cells and the urinary excretion of purine and pyrimidine metabolites were studied in a patient with a T-cell lymphoma (early T-cell phenotype) before and during treatment with deoxycoformycin (dCF; given intravenously [iv] during 3 days, biweekly). During and after the administration of dCF, high amounts of dATP were found in the lymphoid cells and the erythrocytes (maximally, 480 pmol/106 lymphocytes and 5.5 nmol/106 erythrocytes), but not in the polymorphonuclear leukocytes. The amount of dATP in the erythrocytes, however, was significantly lower than described in the literature. During each administration of dCF, the number of blast cells in the peripheral blood rose initially, followed by a rapid decrease. After three courses, a hematologic remission was achieved and maintained for 6 weeks; then an autologous bone-marrow transplantation was performed. During the first dCF course a large amount of deoxyadenosine was found in the urine. During the second course, this excretion was much lower, but still higher than in healthy individuals. In the patient described, dCF showed a highly specific toxicity for the immature T-lymphoblast; hardly any changes were seen in the numbers of the other hematopoietic cells, both in the blood and in the bone marrow.

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Lymphocyte dysfunction caused by deficiencies in purine metabolism

Cited by 29 publications

References 17 publications

Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes.

Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes.

Adenosine and adenosine receptors in immune function. Minireview and meeting report

Biochemical consequences of 2′-deoxycoformycin treatment in a patient with T-cell lymphoma. Some unusual findings

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