Characterization of human lung cancer cells resistant to 4 '-O-demethyl-4 beta-(2 ''-nitro-4 ''-fluoroanilino)-4-desoxypodophyllotoxin, a unique compound in the epipodophyllotoxin antitumor class

Citation
Y. Tachibana et al., Characterization of human lung cancer cells resistant to 4 '-O-demethyl-4 beta-(2 ''-nitro-4 ''-fluoroanilino)-4-desoxypodophyllotoxin, a unique compound in the epipodophyllotoxin antitumor class, ANTI-CANC D, 11(1), 2000, pp. 19-28
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology,"Onconogenesis & Cancer Research
Journal title
ANTI-CANCER DRUGS
ISSN journal
0959-4973 → ACNP
Volume
11
Issue
1
Year of publication
2000
Pages
19 - 28
Database
ISI
SICI code
0959-4973(200001)11:1<19:COHLCC>2.0.ZU;2-4
Abstract
A new semi-synthetic podophyllotoxin derivative, 4'-O-demethyl-4 beta-(2"-n itro-4"-fluoroanilino)-4-desoxypodophyllotoxin (compound 1), an analog of G L-331 (compound 2), is a potent and broad-spectrum inhibitor of cultured hu man cancer and drug-resistant cell growth. In general, 4'-demethylepipodoph yllotoxin analogs, including 2, exert anti-tumor activity by targeting the nuclear enzyme DNA topoisomerase II, but 1 is not an enzyme inhibitor. Unli ke the cytotoxic activity of compound 2, cell killing by 1 is dose-limiting and a significant fraction of cells (30-40%) survive treatment. As an appr oach to investigate mechanism of action, 1-resistant A549 (human lung cance r) sub-lines were selected and characterized. Results of the work show that 1-resistant cells: (i) are moderately cross-resistant (2- to 3-fold) to va rious cytotoxic drugs via a P-glycoprotein-independent mechanism, (ii) have an altered growth habit, (iii) are deficient in normal attachment on plast ic and collagen substrata, and (iv) have an altered plasma membrane protein composition including several proteins in the 140- >200 kDa molecular mass range and a doublet of phosphoserine-containing proteins of about 135 kDa. Since 1 treatment of cells affects neither cellular attachment or membrane -protein phosphorylation, the changes observed in 1-resistant cells are int erpreted as a survival response to drug action. [(C) 2000 Lippincott Willia ms & Wilkins.].