Synergy of inhibition of DNA synthesis in human bone marrow by azidothymidine plus deficiency of folate and/or vitamin B12?

B. C. Herzlich, Mohammad Ranginwala, I. Nawabi, V. Herbert

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The effect of azidothymidine (Zidovudine, AZT) on pyrimidine (thymidine, deoxyuridine, and thymidine triphosphate) incorporation into DNA in folate- and/or vitamin B12-deficient and normal human bone marrow cells was studied to investigate whether such vitamin deficiency affects susceptibility to AZT-induced hematologic toxicity. Bone marrow cells from 12 patients were studied: 5 had folate and/or vitamin B12 deficiency; 7 controls included 5 with anemia related to chronic disease and 2 with iron deficiency. At 0.2 μM AZT (3 hr, 37°C), the approximate pharmacologic serum trough level, pyrimidine incorporation into DNA was suppressed by 12 to 19% in folate- and/or vitamin B12-deficient cells and by 16 to 23% in normal cells. At 2.0 μM AZT (3 hr, 37°C), the approximate pharmacologic serum peak level, this was suppressed by 15 to 40% in folate- and/or vitamin B12-deficient cells and by 32 to 47% in controls. Deoxyuridine incorporation into DNA was inhibited significantly greater than thymidine at 2.0 μM AZT (3 hr, 37°C) in both groups. Inhibition of deoxyuridine incorporation was not reversed with methyltetrahydrofolate or vitamin B12. There tended to be less striking suppression by AZT of deoxyuridine incorporation into DNA in bone marrow cells from vitamin B12-deficient patients, which was made more striking by adding vitamin B12. This suggests that some of what passes for 'AZT' damage to bone marrow cells may in fact be coincident deficiency of vitamin B12. AZT inhibition of DNA synthesis in 3 hr bone marrow cultures is relatively consistent in a variety of hematologic disorders. As approximately two-thirds of AIDS patients appear to be in negative balance with respect to folate and/or vitamin B12, the fact that AZT-induced inhibition of pyrimidine incorporation into DNA is occurring in cells which may be megaloblastic, i.e., in a state of impaired DNA synthesis, suggests that these cells may be more susceptible to AZT toxicity. The data also support the notion that AZT inhibition results predominantly from termination of DNA chain elongation. Whether folate or vitamin B12 supplementation may partially overcome apparent 'AZT inhibition' of DNA synthesis (hematolgic toxicity) and whether the benefit of such therapy exceeds the risk will require further study.

Original languageEnglish (US)
Pages (from-to)177-183
Number of pages7
JournalAmerican Journal of Hematology
Volume33
Issue number3
DOIs
StatePublished - 1990
Externally publishedYes

Fingerprint

Zidovudine
Vitamin B 12
Folic Acid
Bone Marrow
DNA
Bone Marrow Cells
Deoxyuridine
Vitamin B 12 Deficiency
Thymidine
Avitaminosis
Serum
Anemia
Acquired Immunodeficiency Syndrome
Chronic Disease
Iron

Keywords

  • cell proliferation
  • megaloblastic anemia
  • zidovudine

ASJC Scopus subject areas

  • Hematology

Cite this

Synergy of inhibition of DNA synthesis in human bone marrow by azidothymidine plus deficiency of folate and/or vitamin B12? / Herzlich, B. C.; Ranginwala, Mohammad; Nawabi, I.; Herbert, V.

In: American Journal of Hematology, Vol. 33, No. 3, 1990, p. 177-183.

Research output: Contribution to journalArticle

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abstract = "The effect of azidothymidine (Zidovudine, AZT) on pyrimidine (thymidine, deoxyuridine, and thymidine triphosphate) incorporation into DNA in folate- and/or vitamin B12-deficient and normal human bone marrow cells was studied to investigate whether such vitamin deficiency affects susceptibility to AZT-induced hematologic toxicity. Bone marrow cells from 12 patients were studied: 5 had folate and/or vitamin B12 deficiency; 7 controls included 5 with anemia related to chronic disease and 2 with iron deficiency. At 0.2 μM AZT (3 hr, 37°C), the approximate pharmacologic serum trough level, pyrimidine incorporation into DNA was suppressed by 12 to 19{\%} in folate- and/or vitamin B12-deficient cells and by 16 to 23{\%} in normal cells. At 2.0 μM AZT (3 hr, 37°C), the approximate pharmacologic serum peak level, this was suppressed by 15 to 40{\%} in folate- and/or vitamin B12-deficient cells and by 32 to 47{\%} in controls. Deoxyuridine incorporation into DNA was inhibited significantly greater than thymidine at 2.0 μM AZT (3 hr, 37°C) in both groups. Inhibition of deoxyuridine incorporation was not reversed with methyltetrahydrofolate or vitamin B12. There tended to be less striking suppression by AZT of deoxyuridine incorporation into DNA in bone marrow cells from vitamin B12-deficient patients, which was made more striking by adding vitamin B12. This suggests that some of what passes for 'AZT' damage to bone marrow cells may in fact be coincident deficiency of vitamin B12. AZT inhibition of DNA synthesis in 3 hr bone marrow cultures is relatively consistent in a variety of hematologic disorders. As approximately two-thirds of AIDS patients appear to be in negative balance with respect to folate and/or vitamin B12, the fact that AZT-induced inhibition of pyrimidine incorporation into DNA is occurring in cells which may be megaloblastic, i.e., in a state of impaired DNA synthesis, suggests that these cells may be more susceptible to AZT toxicity. The data also support the notion that AZT inhibition results predominantly from termination of DNA chain elongation. Whether folate or vitamin B12 supplementation may partially overcome apparent 'AZT inhibition' of DNA synthesis (hematolgic toxicity) and whether the benefit of such therapy exceeds the risk will require further study.",
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