The ras oncogene-mediated sensitization of human cells to topoisomerase II inhibitor-induced apoptosis.
BACKGROUND
Among the inhibitors of the enzyme topoisomerase II (an important target for chemotherapeutic drugs) tested in the National Cancer Institute's In Vitro Antineoplastic Drug Screen, NSC 284682 (3'-hydroxydaunorubicin) and NSC 659687 [9-hydroxy-5,6-dimethyl-1-(N-[2(dimethylamino)ethyl]carbamoyl)-6H-pyrido -(4,3-b)carbazole] were the only compounds that were more cytotoxic to tumor cells harboring an activated ras oncogene than to tumor cells bearing wild-type ras alleles. Expression of the multidrug resistance proteins P-glycoprotein and MRP (multidrug resistance-associated protein) facilitates tumor cell resistance to topoisomerase II inhibitors. We investigated whether tumor cells with activated ras oncogenes showed enhanced sensitivity to other topoisomerase II inhibitors in the absence of the multidrug-resistant phenotype.


METHODS
We studied 20 topoisomerase II inhibitors and individual cell lines with or without activated ras oncogenes and with varying degrees of multidrug resistance.


RESULTS
In the absence of multidrug resistance, human tumor cell lines with activated ras oncogenes were uniformly more sensitive to most topoisomerase II inhibitors than were cell lines containing wild-type ras alleles. The compounds NSC 284682 and NSC 659687 were especially effective irrespective of the multidrug resistant phenotype. The ras oncogene-mediated sensitization to topoisomerase II inhibitors was far more prominent with the non-DNA-intercalating epipodophyllotoxins than with the DNA-intercalating inhibitors. This difference in sensitization appears to be related to a difference in apoptotic sensitivity, since the level of DNA damage generated by etoposide (an epipodophyllotoxin derivative) in immortalized human kidney epithelial cells expressing an activated ras oncogene was similar to that in the parental cells, but apoptosis was enhanced only in the former cells.


CONCLUSIONS
Activated ras oncogenes appear to enhance the sensitivity of human tumor cells to topoisomerase II inhibitors by potentiating an apoptotic response. Epipodophyllotoxin-derived topoisomerase II inhibitors should be more effective than the DNA-intercalating inhibitors against tumor cells with activated ras oncogenes.
ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702, USA.
H M
HM
Koo
M
M
Gray-Goodrich
G
G
Kohlhagen
M J
MJ
McWilliams
M
M
Jeffers
A
A
Vaigro-Wolff
W G
WG
Alvord
A
A
Monks
K D
KD
Paull
Y
Y
Pommier
G F
GF
Vande Woude
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D011905:Genes, ras / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; C117469:NSC 284682; C117470:NSC 659687; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D003630:Daunorubicin