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Investigational New Drugs

, Volume 1, Issue 3, pp 197–202 | Cite as

The lethal activity and repair inhibition capacity of 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea

  • B. Drewinko
  • L. -Y. Yang
Preclinical

Summary

The survival response of human colorectal carcinoma cells treated in vitro for 1 h with PCNU was characterized by a threshold exponential curve, Dq = 8 μg/ml (1 h) and D 0 = 22 μg/ml (1 h). Continuous treatment induced decreasing degrees of cell kill although PCNU was biologically stable in solution for at least 24 h. Cells treated with PCNU were unable to recover from potentially lethal damage but were quite capable of repairing PCNU-induced sublethal damage. Thus, PCNU with different alkylating and carbamoylating than other nitrosourea congeners had similar cytotoxic and repair inhibition capacities. Any therapeutic gain in the clinical use of PCNU must derive only from its lipophilic properties and not from its superior activity at the cellular level.

Key words

nitrosourea cytotoxicity repair carbamoylation 

Abbreviations

PCNU

1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-1-nitrosourea (NSC 95466)

CCNU

1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC 79037)

BCNU

1,3-bis(2-chloroethyl)-1-nitrosourea (NSC 409962) cis-acid, 4-(3-(2-chloroethyl)-3-nitrosoureido)-cis-cyclohexane-carboxylic acid (NSC 153174)

MeCCNU

1-(2-chloroethyl)-3-trans-(4-methyl-cyclohexyl)-1-nitrosourea (NSC 95441)

PE

plating efficiency

Dq

quasithreshold dose equal to the intercept with the abscissa (at 100% survival) of the exponential part of survival curve

D0

mean lethal dose equal to the concentration required to reduce survival by 63% on exponential part of survival curve

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References

  1. 1.
    A summary of the activity of PCNU, NSC 95466 National Cancer Institute Report, 29 June 1978Google Scholar
  2. 2.
    Burchenal JH, Carter SK: New cancer chemotherapeutic agents. Cancer (Phila.) 30:1639–1646, 1972Google Scholar
  3. 3.
    Carter SK: Current status of new agents. Cancer Chemother Rep 3:337–47, 1972Google Scholar
  4. 4.
    Chabner BA, Myers CE, Coleman CN, Johns DG: The clinical pharmacology of antineoplastic agents. N Engl J Med 292:1107–1113, 1975Google Scholar
  5. 5.
    Crider AM, Lamey R, Floss HG, Cassady JM: Synthesis of nitrosourea derivatives of pyridine and piperidine as potential anticancer agents. J Med Chem 23:848–851, 1980Google Scholar
  6. 6.
    Drewinko B, Barlogie B, Freireich EJ: Response of exponentially growing, stationary-phase, and synchronized cultured human colon carcinoma cells to treatment with nitrosourea derivatives. Cancer Res 39:2630–2636, 1979Google Scholar
  7. 7.
    Drewinko B, Bobo B, Roper PR, Malahy MA, Barlogie B, Jonson B: Analysis of the growth kinetics of a human lymphoma cell line. Cell Tissue Kinet 11:177–191, 1978Google Scholar
  8. 8.
    Drewinko B, Green C, Loo TL: Cellular response to treatment with 4-(3-(2-chloroethyl)-3-nitrosoureido)cis cyclohexanecarboxylic acid, a water soluble nitrosourea derivative. Cancer Treat Rep 61:1513–1518, 1977Google Scholar
  9. 9.
    Drewinko B, Loo TL, Gottlieb JA: A comparison of the lethal effects of three nitrosourea derivatives on cultured human lymphoma cells. Cancer Res 36:511–515, 1976Google Scholar
  10. 10.
    Drewinko B, Romsdahl MM, Yang L-Y, Ahearn MJ, Trujillo JM: Establishment of a human carcinoembryonic antigen-producing colon adenocarcinoma cell line. Cancer Res 36:467–475, 1976Google Scholar
  11. 11.
    Drewinko B, Roper PR, Barlogie B: Patterns of cell survival following treatment with antitumor agents in vitro. Eur J Cancer 15:93–99, 1979Google Scholar
  12. 12.
    Drewinko B, Yang L-Y, Barlogie B, Romsdahl MM, Meistrich M, Malahy MA, Giovanella B: Further biological characteristics of a human carcinoembryonic antigen-producing colon carcinoma cell line. J Natl Cancer Inst 61: 75–83, 1978Google Scholar
  13. 13.
    Heal MH, Fox PA, Schein PS: Effect of carbamoylation on the repair of nitrosourea-induced DNA alkylation damage in Li210 cells. Cancer Res 39:87–89, 1979Google Scholar
  14. 14.
    Hill DL, Kirk MD, Struck RF: Microsomal metabolism of nitrosoureas. Cancer Res 35:295–301, 1975Google Scholar
  15. 15.
    Hill RP, Stanley JA: The response of hypoxic B16 melanoma cells to in vivo treatment with chemotherapeutic agents. Cancer Res 35:1147–1153, 1975Google Scholar
  16. 16.
    Kann HC: Comparison of biochemical and biological effects of four nitrosoureas with differing carbamoylating activities. Cancer Res 38:2363–2366, 1978Google Scholar
  17. 17.
    Kann HE, Kohn KW, Lyles JM: Inhibition of DNA repair by the 1,3-bis(2-chlorethyl)-1-nitrosourea breakdown product, 2-chloroethyl isocyanate. Cancer Res 34:398–402, 1974Google Scholar
  18. 18.
    Little JB: Repair of potentially lethal radiation damage in mammalian cells: enhancement by conditioned medium from stationary cultures. Int J Radiat Biol Relat Stud Phys Chem Med 20:87–92, 1971Google Scholar
  19. 19.
    Oliverio VT: Toxicology and pharmacology of the nitrosoureas. Cancer Chemother Rep 4:13–20, 1973Google Scholar
  20. 20.
    Report NSC-95466. Urea,-1-(2-chloroethyl-3-(2,6-dioxo-1-piperidyl)-nitroso. National Cancer Institute Report MR1KC-PT-3809-77-12, March 1978Google Scholar
  21. 21.
    Schmidt LH: A study of the pharmacology of potential antileukemia and other anticancer drugs administered alone or in combination. Annual Progress Report, pp. 45–54. Birmingham, Ala., Southern Research Institute, 1970Google Scholar
  22. 22.
    Sponzo RW, DeVita VT, Oliverio VT: Physiologic disposition of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 1-(2-chloroethyl)-3-(4-Methyl cyclohexyl)-1-nitrosourea (MeCCNU) in man. Cancer (Phila) 31:1154–1159, 1973Google Scholar
  23. 23.
    Stewart DJ, Benjamin RS, Laevens M, Valdivieso M, Burgess A, Bodey GP: Phase I study of 1-(2-chloroethyl)-3-(2,6-Dioxo-3-piperidyl)-1-nitrosourea) (PCNU, NSC-95466) in adults with solid tumors. Cancer Res 40: 3750–3754, 1980Google Scholar
  24. 24.
    Wasserman TH, Slavik M, Carter SK: Clinical comparison of the nitrosourea. Cancer (Phila) 36:1258–1266, 1975Google Scholar
  25. 25.
    Wheeler GP: Studies related to the mechanisms of action of cytotoxic alkylating agents. A review. Cancer Res 22:651–688, 1962Google Scholar
  26. 26.
    Wheeler GP, Bowdon BJ, Grimsley JA, Lloyd HH: Interrelationships of some chemical physiocochemical, and biological activities of several 1(2-haloethyl)-1-nitrosourea. Cancer Res 34:194–200, 1974Google Scholar

Copyright information

© Martinus Nijhoff Publishers 1983

Authors and Affiliations

  • B. Drewinko
    • 1
  • L. -Y. Yang
    • 1
  1. 1.Department of Laboratory MedicineThe University of Texas System Cancer Center M.D. Anderson Hospital and Tumor InstituteHoustonUSA

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