Growth inhibitory effects of antifolates against an adriamycin-resistant human small cell lung cancer cell line.
We have established an Adriamycin (ADM)-resistant small cell lung cancer (SCLC) cell line, SBC-3/ADM 100, which shows multifactorial mechanisms of resistance to ADM, such as over-expression of P-glycoprotein, an enhanced detoxifying system and a decrease in topoisomerase II activity. In the present study, we confirmed that SBC-3/ADM 100 showed collateral sensitivity to methotrexate and TNP-351, a new antifolate, though this cell line showed a typical multidrug resistance (MDR) pattern. We also demonstrated a faster uptake and higher accumulation (1.3-fold) of TNP-351 in the SBC-3/ADM 100 cells than those in the parent SBC-3 cells. These results explain one of the mechanisms for collateral sensitivity in the resistant cells. Furthermore, this cell line was found to have no cross-resistance to edatrexate and minimal cross-resistance to trimetrexate, 254-S (cisplatin analog), 5-fluorouacil and 4-hydroperoxyifosfamide. These drugs will have clinical importance in patients with SCLC who were previously treated with an ADM-containing regimen. Thus, antifolates, especially TNP-351 and edatrexate, can be expected to eradicate residual multidrug resistant SCLC cells selected by ADM.
Matsuo
K
K
Second Department of Internal Medicine, Okayama University Medical School, Japan.
Kiura
K
K
Ueoka
H
H
Tabata
M
M
Shibayama
T
T
Matsumura
T
T
Takigawa
N
N
Hiraki
S
S
Harada
M
M
D000818:Animals; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy*; D008727:Methotrexate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D014407:Tumor Cells, Cultured
D005493:Folic Acid Antagonists; D006131:Growth Inhibitors; C078101:TNP 351; D004317:Doxorubicin; D008727:Methotrexate