STRUCTURE-DEPENDENT ANTITUMOR ACTIVITIES OF NOVEL ANTHRACYCLINES YM1,YM3, YM4 AND YM6 - DRUG TRANSPORT-PROPERTIES AND EFFECTS ON BIOMACROMOLECULE SYNTHESIS IN DRUG-SENSITIVE AND RESISTANT LEUKEMIA-CELLS
Xr. Jiang et al., STRUCTURE-DEPENDENT ANTITUMOR ACTIVITIES OF NOVEL ANTHRACYCLINES YM1,YM3, YM4 AND YM6 - DRUG TRANSPORT-PROPERTIES AND EFFECTS ON BIOMACROMOLECULE SYNTHESIS IN DRUG-SENSITIVE AND RESISTANT LEUKEMIA-CELLS, Journal of chemotherapy, 5(5), 1993, pp. 334-343
The antitumor activities of four novel doxorubicin (DOX) analogues, YM
1, YM3, YM4 and YM6 in relation to their structure and drug transport
properties, have been investigated in U937 monocytic and CCRF-CEM lymp
hoid drug sensitive leukemia cell lines, as well as in CEM/VLB(100), a
drug resistant subline displaying high levels of P-glycoprotein. Trea
tment of all cell lines with YM1, 3, 4 and 6 produced a dose dependent
decrease in DNA, RNA and protein synthesis as measured by [H-3]-thymi
dine, [H-3]-uridine and [H-3]-leucine uptake respectively. YM1 was mor
e effective than YM3, YM4 or YM6 against the drug sensitive cells. The
antitumor effects of all these DOX-analogues on macromolecule synthe
sis in U937 and CCRF-CEM cells were lower than that of DOX and epirubi
cin (EDR). A rapid accumulation of the novel anthracyclines was found
in all cell lines compared with DOX or EDR. However, the maximal accum
ulation of the DOX analogues was lower than that of EDR. There is a gr
eater efflux from CCRF-CEM sensitive cells and less from CEM/VLB(100)
resistant cells of the DOX-derivatives when compared with EDR and DOX.
Drug-induced cytotoxicity significantly correlated (P < 0.05) with dr
ug retention levels in CCRF-CEM and U937 drug sensitive cells as indic
ated by an inverse correlation curve between anthracycline retention a
nd drug induced IC50 value. It was demonstrated that an increased leve
l of drug retained within the sensitive cells would therefore produce
a more cytotoxic effect of the drug. However, no such correlation was
observed in CEM/VLB(100) resistant cells. YM3 was shown to have an inc
reased antitumor activity against CEM/VLB(100) resistant cells compare
d with DOX with a lower resistance factor. These results showed that t
he antitumor effects of four novel DOX-analogues, like DOX or EDR, wer
e associated with inhibition of DNA replication, transcription and tra
nslation. The finding that resistant leukemic cells are more susceptib
le to the cytotoxic effect of YM13 than DOX warrants further investiga
tion to identify the intrinsic mechanism of resistance.