Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 34, Issue 2, pp 103–108 | Cite as

In vitro characterization of the myelotoxicity of cyclopentenyl cytosine

  • Donna A. Volpe
  • De-lin Du
  • Charles K. Grieshaber
  • Martin J. MurphyJr.
Original Articles Cyclopentenyl Cytosine, CPE-C, Myelotoxicity, In Vitro, Human, Murine

Abstract

We studied the toxicity of a new experimental anticancer drug, cyclopentenyl cytosine (CPE-C), to human and murine hematopoietic progenitor cells in vitro. Due to CPE-C's in vivo myelotoxicity, it was important to characterize its potential adverse effects on human marrow cells during preclinical development of the drug. Marrow cells were exposed to CPE-C for either 1 h prior to addition in clonal assays or continuously during their culture period. The inhibitory effects of CPE-C on myeloid (CFU-gm) and erythroid (CFU-e, BFU-e) colony formation were concentration-and time-dependent, with continuous CPE-C exposure being significantly more inhibitory than 1-h exposure. The results of both exposure experiments were combined to investigate colony inhibition as a function of overal drug exposure (concentration x time, AUC) and data analyzed by the nonlinear Emax equation. Human and murine CFU-gm had similar AUC-response curves and IAUC70 values (i.e., AUC at 70% colony inhibition) of 40.8 and 41.9 μMh, respectively. In contrast, murine CFU-e and BFU-e were more sensitive to CPE-C, having lower IAUC70 values (both, 21.1 μMh) than human CFU-e and BFU-e (107.8 and 33.0 μMh, respectively). This difference was most prominent with the late erythroid progenitor, CFU-e, in that the human cells were 5 times more resistant to inhibition by CPE-C. CPE-C was myelotoxic in vitro to human and murine marrow cells and toxicity correlated with overall drug exposure.

Keywords

Overal Marrow Cell Drug Exposure Hematopoietic Progenitor Hematopoietic Progenitor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bhalla K, MacLaughlin W, Cole J, Arlin Z, Baker M, Graham G, Grant S (1987) Deoxycytidine preferentially protects normal versus leukemic myeloid progenitor cells from cytosine arabinoside-mediated cytotoxicity. Blood 70: 568–571Google Scholar
  2. 2.
    Blaney SM, Balis FM, Hegedus L, Heideman RL, McCully C, Murphy RF, Kelley JA, Poplack DG (1990) Pharmacokinetics and metabolism of cyclopentenyl cytosine in nonhuman primates. Cancer Res 50: 7915–7919Google Scholar
  3. 3.
    Burgess AW, Wilson EM, Metcalf D (1977) Stimulation by human placental conditioned medium of hematopoietic colony formation by human marrow cells. Blood 49: 573–583Google Scholar
  4. 4.
    Collins JM, Grieshaber CK, Chabner BA (1990) Pharmacologically guided phase I clinical trials based upon preclinical drug development. J Natl Cancer Inst 82: 1321–1326Google Scholar
  5. 5.
    Cooney DA, Rommel ME, Kang G, Wilson Y, Tseng J, Johns DG (1990) Cellular pharmacology in human cells of cyclopentenyl cytosine, a new antineoplastic nucleoside (abstract). Proc Am Assoc Cancer Res 31: 421Google Scholar
  6. 6.
    Du DL, Volpe DA, Murphy MJ (1989) Microcapillary clonogenic assays for human marrow hematopoietic progenitor cells. Int J Cell Cloning 7: 303–313Google Scholar
  7. 7.
    Ford H, Cooney DA, Ahluwalia GS, Hao Z, Rommel ME, Hicks L, Dobyn KA, Tomaszewski JE, Johns DG (1991) Cellular pharmacology of cyclopentenyl cytosine in Molt-4 lymphoblasts. Cancer Res 51: 3733–3740Google Scholar
  8. 8.
    Ford H, Cooney DA, Dobyns KA, Rommel ME, Johns DG (1991) Time-dependence of cytidine rescue from the cytotoxicity of cyclopentenyl cytosine (abstract). Proc Am Assoc Cancer Res 32: 414Google Scholar
  9. 9.
    Gallicchio VS, Murphy MJ (1979) In vitro erythropoiesis. II. Cytochemical enumeration of erythroid stem cells (CFU-e and BFU-e) from normal mouse and human hematopoietic tissues. Exp Hematol 7: 219–224Google Scholar
  10. 10.
    Glazer RI, Knode MC, Lim MI, Marquez VE (1985) Cyclopentenyl cytidine analogue. An inhibitor of cytidine triphosphate synthesis in human colon carcinoma cells. Biochem Pharmacol 34: 2535–2539Google Scholar
  11. 11.
    Glazer RI, Cohen MB, Hartman KD, Knode MC, Lim MI, Marquez VE (1986) Induction of differentiation in the human promyelocytic leukemia cell line HL-60 by the cyclopentenyl analogue of cytidine. Biochem Pharmacol 35: 1841–1848Google Scholar
  12. 12.
    Holford NHG, Sheiner LB (1981) Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 6: 429–453Google Scholar
  13. 13.
    Johnson GR, Metcalf D (1977) Pure and mixed erythroid colony formation in vitro stimulated by spleen-conditioned medium with no detectable erythropoietin. Proc Natl Acad Sci USA 74: 3879–3882Google Scholar
  14. 14.
    Kang GJ, Cooney DA, Moyer JD, Kelley JA, Kim HY, Marquez VE, Johns DG (1989) Cyclopentenylcytosine triphosphate: formation and inhibition of CTP synthetase. J Biochem Chem 264: 713–718Google Scholar
  15. 15.
    Lim MI, Moyer JD, Cysyk RL, Marquez VE (1984) Cyclopentenyluridine and cyclopentenylcytidine analogues as inhibitors of uridine-cytidine kinase. J Med Chem 27: 1536–1538Google Scholar
  16. 16.
    Marquez VE, Lim MI, Treanor SP, Plowman J, Priest MA, Markovac A, Khan MS, Kaskar B, Driscoll JS (1988) Cyclopentenylcytosine. A carbocyclic nucleoside with antitumor and antiviral properties. J Med Chem 31: 1687–1694Google Scholar
  17. 17.
    McLeod DL, Shreeve MM, Axelrad AA (1974) Improved plasma culture system for production of erythrocytic colonies in vitro: quantitative assay method for CFU-E. Blood 44: 517–534Google Scholar
  18. 18.
    Moyer JD, Malinowski NM, Treanor SP, Marquez VE (1986) Antitumor activity and biochemical effects of cyclopentenyl cytosine in mice. Cancer Res 46: 3325–3329Google Scholar
  19. 19.
    Murphy MJ, Sullivan ME (1978) Culture of erythroid stem cells from murine and human marrow and blood. In: Murphy MJ (ed) In vitro aspects of erythropoiesis. Springer, New York Berlin Heidelberg, pp 262–265Google Scholar
  20. 20.
    Muus P, Haanen C, Raijmakers R, deWitte T, Salden M, Wessels J (1987) Influence of dose and duration of exposure on the cytotoxic effect of cytarabine toward human hematopoietic clonogenic cells. Semin Oncol 14 [Suppl 2]: 238–244Google Scholar
  21. 21.
    Page JG, Heath JE, Sparks RM, Kelley JA, Tomaszewski JE (1991) Preclinical toxicology studies of cyclopentenylcytosine (CPEC; NSC-375575) given by continuous intravenous infusion to beagle dogs (abstract). Proc Am Assoc Cancer Res 32: 423Google Scholar
  22. 22.
    Parchment RE, Volpe DA, LoRusso PM, Erickson-Miller CL, Murphy MJ, Grieshaber CK (1994) An in vivo-in vitro correlation of the myelotoxicity of 9-methoxypyrazoloacridine (PZA, NSC-366140, PD115934) to myeloid and erythroid hematopoietic progenitors from human, murine and canine marrow. J Natl Cancer Inst 86: 273–280Google Scholar
  23. 23.
    Politi P, Setser A, Bastian A, Ford H, Xie F, Kelley J, Jordan E, Dahut B, Allegra C, Hamilton JM, Arbuck S, Chen A, Agbaria R, Grem J (1993) Pharmacologically guided phase I trial of cyclopentenyl cytosine (CPE-C) with biochemical monitoring (abstract). Proc Am Soc Clin Oncol 12: 142Google Scholar
  24. 24.
    Raijmakers R, deWitte T, Linssen P, Wessels T, Haanen C (1986) The relation of exposure time and drug concentration in their effect on cloning efficiency after incubation of human bone marrow with cytosine arabinoside. Br J Haematol 62: 447–453Google Scholar
  25. 25.
    Sheridan JW, Metcalf D (1972) A low molecular weight factor in lung-conditioned medium stimulating granulocyte and monocyte colony formation in vitro. J Cell Physiol 81: 11–24Google Scholar
  26. 26.
    Tepe P, Hassenbusch SJ, Benoit R, Anderson JH (1991) BCNU stability as a function of ethanol concentration and temperature. J Neurooncol 10: 121–127Google Scholar
  27. 27.
    Tomaszewski JE, Heath JE, Grieshaber CK, Page JG (1990) Toxicity of cyclopentenylcytosine (CPEC, NSC-375575) in CD2F1 mice and Fischer-344 rats (abstract). Proc Am Assoc Cancer Res 31: 441Google Scholar
  28. 28.
    Volpe DA, Du DL, Pohl KP, Campbell KP, Murphy MJ (1991) Utility of human bone marrow obtained incidental to orthopedic surgery for hematopoietic clonal assays. Pathobiology 59: 53–56Google Scholar
  29. 29.
    Yee LK, Allegra CJ, Trepel JB, Grem JL (1992) Metabolism and RNA incorporation of cyclopentenyl cytosine in human colorectal cancer cells. Biochem Pharmacol 43: 1587–1599Google Scholar
  30. 30.
    Zaharko DS, Kelley JA, Tomaszewski JE, Hegedus L, Hartman NR (1990) Cyclopentenyl cytosine: interspecies predictions based on rodent plasma and urine kinetics. Invest New Drugs 9: 9–18Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Donna A. Volpe
    • 1
  • De-lin Du
    • 1
  • Charles K. Grieshaber
    • 2
  • Martin J. MurphyJr.
    • 1
  1. 1.Hipple Cancer Research CenterDaytonUSA
  2. 2.National Cancer InstituteBethesdaUSA

Personalised recommendations