Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Deoxycoformycin toxicity in mice after long-term treatment

Summary

Deoxycoformycin, a tight-binding inhibitor of the enzyme adenosine deaminase, is a potent lymphocytotoxic agent. To examine the effect of deoxycoformycin on mouse tissues the drug was administered IP either by single or by repeated injections at one of two dose levels (0.2 or 10.0 mg/kg). Treatment with repeated injections at the higher dose caused retardation of growth and increases in lung and splenic mass. Body temperature, hematocrit, and total leukocyte count remained constant. Single injections at the lower dose caused complete inhibition of adenosine deaminase in liver and blood, and partial inhibition in jejunum and spleen, but at the higher dose complete inhibition of the enzyme in all tissues was obtained. Dosage appeared to have no effect on the rate of recovery of the deoxycoformycin-inhibited enzyme but marked tissue differences were observed. The enzymic activity recovered rapidly in jejunum (100% in 1 day) but slowly in other tissues (after 28 days, about 60% in spleen and liver; about 85% in kidney and blood, and 100% in lungs). These observations suggest that the recovery of inhibited enzyme depends largely upon the rate of proliferation of cells and protein synthesis. These tissue differences in recovery rates may play a role in the pharmacological and chemotherapeutic behavior of this drug.

This is a preview of subscription content, log in to check access.

Abbreviations

ADA:

adenosine deaminase (adenosine aminohydrolase, E.C. 3.5.4.4.)

DCF:

2-deoxycoformycin [3-(2′-deoxy-β-d-erythro-pentofuranosyl)-3,6,7,8-tetra-hydroimidazo (4,5-d) (1,3)-diazepin-8-(R)-ol] or Pentostatin

References

  1. 1.

    Agarwal RP (1979) Recovery of 2′-deoxycoformycin-inhibited adenosine deaminase of mouse erythrocytes and leukemia L1210 in vitro. Cancer Res 39:1425

  2. 2.

    Agarwal RP (1980) In vivo inhibition of adenosine deaminase by 2′-deoxycoformycin in mouse blood and leukemia L1210 cells. Biochem Pharmacol 29:187

  3. 3.

    Agarwal RP, Spector T, Parks RE Jr (1977) Tight-binding inhibitors. IV. Inhibition of adenosine deaminase by various inhibitors. Biochem Pharmacol 26:359

  4. 4.

    Benjamin RS, Plunkett W, Keating MJ, Feun LG, Hug V, Nelson JA, Bodey GP, Freireich EJ (1980) Phase I and biochemical pharmacological studies of deoxycoformycin. Proc Am Assoc Cancer Res 21:337

  5. 5.

    Cummings FJ, Crabtree GW, Spremulli E, Rogler-Brown T, Parks RE Jr, Calabresi P (1980) Studies with 2′-deoxycoformycin in man and subhuman primates. Proc Am Assoc Cancer Res 21:332

  6. 6.

    Grever M, Miser J, Balcerzak S, Neidhart J (1980) Ablation of adenosine deaminase activity by deoxycoformycin induced cell lysis in refractory leukemia. Proc Am Assoc Cancer Res 21:335

  7. 7.

    Kufe D, Major P, Agarwal R, Reinherz E, Frei E III (1980) Phase I–II trial of deoxycoformycin (DCF) in T-cell malignancies. Proc Am Assoc Cancer Res 21:328

  8. 8.

    LePage GA, Worth LS, Kimbal AP (1976) Enhancement of the anti-tumour activity of arabinofuranosyladenine by 2′-deoxycoformycin. Cancer Res 36:1481

  9. 9.

    Rogler-Brown T, Agarwal RP, Parks RE Jr (1978) Tight-binding inhibitors. VI. The interaction of deoxycoformycin and adenosine deaminase in intact human erythrocytes and sarcoma-180 cells. Biochem Pharmacol 27:2289

  10. 10.

    Schneider R, Korngold G, Vale K, Woodcock T, Tan C, Young C (1980) Clinical and pharmacological investigation of deoxycoformycin. Proc Am Assoc Cancer Res 21:185

  11. 11.

    Smyth JF, Young RC, Young DM (1978) In vivo toxicity to lymphoid tissue by 2′-deoxycoformycin. Cancer Chemother Pharmacol 1:49

  12. 12.

    Smyth JF, Chassin MM, Harrap KR, Adamson RH, Johns DG (1979) 2′-Deoxycoformycin (DCF): Phase I trial and clinical pharmacology. Proc Am Assoc Cancer Res 20:47

  13. 13.

    Trotta PP, Ahland MP, Brown GF, Balis ME (1978) Studies on the effect of infusion of enzyme inhibitors on mouse adenosine deaminase. Mol Pharmacol 14:199

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Agarwal, R.P. Deoxycoformycin toxicity in mice after long-term treatment. Cancer Chemother. Pharmacol. 5, 83–87 (1980). https://doi.org/10.1007/BF00435409

Download citation

Keywords

  • Adenosine
  • Protein Synthesis
  • Body Temperature
  • Dose Level
  • Recovery Rate