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
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
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.].