Abstract
DNA topoisomerase I (top I) is the target of the antitumor drug camptothecin (CPT) and its analogs. CPT induces dose- and time-dependent degradation of top I. Degradation of top I also occurs in a CPT-resistant cell line and, therefore, is not a consequence of cell death. Top I degradation is preceded by the appearance of a high molecular weight ladder of top I immunoreactivity and can be blocked by specific inhibitors of the proteasome. We compared the effects of five top I poisons [CPT, topotecan, 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(β-d-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB506), camptothecin-(para)-4β-amino-4′-O-demethyl Epipodophyllotoxin (W1), and camptothecin-(ortho)-4β-amino-4′-O-demethyl Epipodophyllotoxin (W2)] on cleavable complex formation and top I degradation. Although all five drugs induced cleavable complex formation, two of the drugs, NB506 and W1 did not induce top I degradation.
Footnotes
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Send reprint requests to: Dr. Yung-Chi Cheng, Yale University, School of Medicine, Department of Pharmacology, 333 Cedar St., New Haven, CT 06520. E-mail: cheng.lab{at}yale.edu
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1 This work was supported by National Institutes of Health Grant T32CA09085
- Abbreviations:
- CPT
- camptothecin
- TPT
- topotecan
- top I
- topoisomerase I
- top II
- topoisomerase II
- NB506
- 6-N-formylamino-12,13-dihydro- 1,11-dihydroxy-13-(β-d-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione
- MG132
- carbobenzoxyl-l-leucyl-l-leucyl-l-leucinal
- E64
- trans-epoxysuccinyl-l-leucylamido-(4-guanidino)butane
- IBU
- i-BuNH-Eps-Leu-Pro-OH
- W1
- camptothecin-(para)-4β-amino-4′-O-demethyl Epipodophyllotoxin
- W2
- camptothecin-(ortho)-4β-amino-4′-O-demethyl Epipodophyllotoxin
- APH
- aphidicolin
- PLDB Protein-linked DNA break
- DCI 3, 4-dichloroisocoumarin
- TPCK tosyl-phenylalanine choromethyl ketone
- YVAD-CMK Ac-Tyr-Val-Ala-Asp-Chloromethyl ketone
- PAGE
- polyacrylamide gel electrophoresis
- VP-16
- 4β-amino-4′-O-demethyl epipodophyllotoxin
- Received October 8, 1998.
- Accepted December 29, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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