This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Gupta, R. S. Search for Related Content PubMed PubMed Citation Articles by Gupta, R. S.

Podophyllotoxin-resistant Mutants of Chinese Hamster Ovary Cells: Cross-Resistance Studies with Various Microtubule Inhibitors and Podophyllotoxin Analogues¹

Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

The cross-resistances of several mutants of Chinese hamster ovary cells which have been obtained after one and two selection steps in the presence of the microtubule inhibitor podophyllotoxin (Pod^RI and Pod^RII mutants, respectively) towards various other inhibitors of microtubule assembly (e.g., colchicine, Colcemid, vinblastine, griseofulvin, maytansine, steganacin, nocodazole, and taxol) have been examined. Based upon their specific patterns of cross-resistance/sensitivity to various microtubule inhibitors, both the Pod^RI and Pod^RII classes of mutants appear to be of more than one kind. Studies on the binding of [³H]podophyllotoxin to cytoplasmic extracts indicate that one of the Pod^RII mutants which has been shown previously to be affected in a M_r 66,000 to 68,000 microtubule-associated protein shows reduced binding of the drug in comparison to the parental Pod^S and Pod^RI cells. The different Pod^RI and Pod^RII mutants exhibited proportionally increased cross-resistances to various podophyllotoxin analogues (e.g., deoxypodophyllotoxin, epipodophyllotoxin, β-peltatin, 4'-demethylpodophyllotoxin, -peltatin, podophyllotoxin-β-D-glucoside, β-peltatin-β-D-glucoside, picropodophyllotoxin, and podophyllic acid) which possess microtubule-inhibitory activity. However, with the exception of one Pod^RI class of mutant, none of the mutants exhibited any cross-resistance to 4'-demethylepipodophyllotoxin thenylidine-β-D-glucoside and 4'-demethylepipodophyllotoxin ethylidine-β-D-glucoside, the 2 podophyllotoxin analogues which lack microtubule-inhibitory activity. The cross-resistance studies with these mutants, which, based upon the biochemical studies and their highly specific patterns of cross-resistance, are presumably affected in microtubules, provide some very novel insights into the mechanisms of action of various microtubule inhibitors. The results presented in this paper also show that the cross-resistance studies with the set of podophyllotoxin-resistant mutants provide a sensitive and highly specific screening procedure for identifying compounds which possess podophyllotoxin-like activity and for investigating the structure-activity relationship among them. The results of structure-activity relationship studies for the various podophyllotoxin analogues examined are discussed.

¹ Work supported by a research grant from the Medical Research Council of Canada.

Received 5/ 3/82. Accepted 10/28/82.

This article has been cited by other articles:

				S. Linder, M. C. Shoshan, and R. S. Gupta Picropodophyllotoxin or Podophyllotoxin Does Not Induce Cell Death via Insulin-like Growth Factor-I Receptor Cancer Res., March 15, 2007; 67(6): 2899 - 2899. [Full Text] [PDF]

				J. B. Kunz, H. Schwarz, and A. Mayer Determination of Four Sequential Stages during Microautophagy in Vitro J. Biol. Chem., March 12, 2004; 279(11): 9987 - 9996. [Abstract] [Full Text] [PDF]

				M. Bloch and K. Johnson Identification of a molecular chaperone in the eukaryotic flagellum and its localization to the site of microtubule assembly J. Cell Sci., January 11, 1995; 108(11): 3541 - 3545. [Abstract] [PDF]