This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bhuyan, B. K. Articles by McGovren, J. P. Search for Related Content PubMed PubMed Citation Articles by Bhuyan, B. K. Articles by McGovren, J. P.

Lethality, DNA Alkylation, and Cell Cycle Effects of Adozelesin (U-73975) on Rodent and Human Cells

Cancer and Infectious Diseases Research, The Upjohn Company, Kalamazoo, Michigan 49001

Adozelesin (U-73975) is an extremely potent cytotoxic agent which causes 90% lethality, after 2 h exposure in vitro, of Chinese hamster ovary and lung (CHO and V79), mouse melanoma (B16), and human ovarian carcinoma (A2780) cells at 0.33, 0.19, 0.2, and 0.025 ng/ml, respectively. Under similar conditions, Adriamycin and cisplatin had 90% lethality values in CHO cells of 150 ng/ml (=249 nM) and 6800 ng/ml (=2266 nM), respectively. The relative drug sensitivity of the cell lines (A2780 > V79, B16, CHO) was correlated to the relative amounts of [³H]adozelesin alkylated to DNA. The greater sensitivity of A2780 was due to (a) greater DNA alkylation at different drug doses and (b) greater intrinsic sensitivity of A2780 which resulted in greater cell kill at comparable DNA alkylation.

Phase specific toxicity studies show that adozelesin was least lethal to CHO cells in mitosis and very early G₁. Lethality increased as cells progressed through G₁ and was maximal in late G₁ and early S. Mitotic cells had lower drug uptake and correspondingly less drug binding to DNA than G₁ or S-phase cells. However, based on the amount of drug alkylated per µg of DNA, cells in M, G₁, and S were equally sensitive. Therefore, the lower sensitivity of M-phase cells was due to lower drug uptake.

Adozelesin had three different effects on progression of CHO, V79, B16, and A2780 through the cell cycle: (a) slowed progression through S which resulted in significantly increasing the percentage of S-phase cells. This effect was transient; (b) cell progression was blocked in G₂ for a long time period; (c) the response of the cell lines to the G₂ block differed. CHO and V79 cells escaped G₂ block by dividing and entered the diploid DNA cycle or did not undergo cytokinesis and became tetraploid. On the contrary, B16 and A2780 cells remained blocked in G₂ and did not become tetraploid. Cell progression was inhibited in a similar manner when a synchronized population of M, G₁, or S-phase cells were exposed to adozelesin.

¹ To whom requests for reprints should be addressed.

Received 4/21/92. Accepted 8/ 4/92.

This article has been cited by other articles:

				M.-B. Yin, Z.-R. Li, S. Cao, F. A. Durrani, R. G. Azrak, C. Frank, and Y. M. Rustum Enhanced 7-Ethyl-10-hydroxycamptothecin (SN-38) Lethality by Methylselenocysteine Is Associated with Chk2 Phosphorylation at Threonine-68 and Down-Regulation of Cdc6 Expression Mol. Pharmacol., July 1, 2004; 66(1): 153 - 160. [Abstract] [Full Text] [PDF]

				S. Bai and D. W. Goodrich Different DNA lesions trigger distinct cell death responses in HCT116 colon carcinoma cells Mol. Cancer Ther., May 1, 2004; 3(5): 613 - 620. [Abstract] [Full Text] [PDF]

				P.-r. Cao, M. M. McHugh, T. Melendy, and T. Beerman The DNA Minor Groove-alkylating Cyclopropylpyrroloindole Drugs Adozelesin and Bizelesin Induce Different DNA Damage Response Pathways in Human Colon Carcinoma HCT116 Cells Mol. Cancer Ther., July 1, 2003; 2(7): 651 - 659. [Abstract] [Full Text] [PDF]

				F. Blanchard, M. E. Rusiniak, K. Sharma, X. Sun, I. Todorov, M. M. Castellano, C. Gutierrez, H. Baumann, and W. C. Burhans Targeted Destruction of DNA Replication Protein Cdc6 by Cell Death Pathways in Mammals and Yeast Mol. Biol. Cell, May 1, 2002; 13(5): 1536 - 1549. [Abstract] [Full Text] [PDF]

				M. Weinberger, P. A. Trabold, M. Lu, K. Sharma, J. A. Huberman, and W. C. Burhans Induction by Adozelesin and Hydroxyurea of Origin Recognition Complex-dependent DNA Damage and DNA Replication Checkpoints in Saccharomyces cerevisiae J. Biol. Chem., December 10, 1999; 274(50): 35975 - 35984. [Abstract] [Full Text] [PDF]

				R. J. Cobuzzi Jr., W. C. Burhans, and T. A. Beerman Inhibition of Initiation of Simian Virus 40DNA Replication in Infected BSC-1 Cells by the DNA Alkylating Drug Adozelesin J. Biol. Chem., August 16, 1996; 271(33): 19852 - 19859. [Abstract] [Full Text] [PDF]