Resistance of mouse cells to the folate analog, methotrexate, results from selection of increasingly resistant cells on progressive increases of methotrexate in the culture medium. High-level resistance is associated with high rates of synthesis of dihydrofolate reductase and correspondingly high numbers of reductase genes. In some variants high resistance and gene copy number are stable in the...

Genetic transformation of murine bone marrow stem cells to methotrexate resistance was achieved using a modified calcium phosphate-DNA coprecipitation procedure. Bone marrow cells were transformed by DNA derived from methotrexate-resistant mouse 3T6 cells. In vivo selection of drug-resistant bone marrow cells resulted from thrice weekly injections of methotrexate (MTX) for a period of 6-8 wk. F...

BDF1 mice bearing L1210 leukemia, when treated with a regimen of uracil and methotrexate, show an increase in survival time greater than when treated with methotrexate alone. The uracil and methotrexate regimen also delays the development of methotrexate resistance as L1210 leukemia is transferred with therapy through multiple generations of mice. When uracil is applied to multiple generations ...

multidrug resistance (mdr) is a complex phenomenon in which many different genes regulating drug transport, cellular repair, detoxification and drug metabolism are involved. nevertheless, in most drug resistant cell lines and cancer patients up-regulation of abc-transporter genes such as mdr associated protein (mrp1) gene could be at the basis of the drug resistance phenotype. we aimed to decre...

Multidrug-resistance-associated protein, MRP8/ABCC11 (ABCC11), is an efflux pump for nucleotide analogues and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). To test whether ABCC11 directly confers 5-fluorouracil (5-FU) resistance, we used the 5-FU-resistant subline PC-6/FU23-26 selected from PC-6 human small-cell lung cancer cells by 5-FU and found that it increases the resistance by approx...

A human fibrosarcoma cell line, HT-1080, and four new cell lines (HS-16, HS-28, HS-30, and HS-42) were established from untreated patients with mesenchymal chondrosarcoma, peripheral nerve sheath sarcoma, malignant hemangiopericytoma, and mixed mesodermal tumor, respectively, and were used for analysis of mechanisms of intrinsic resistance to methotrexate. All four new cell lines were resistant...

Three human squamous carcinoma cell lines (FaDu, A253, and SQCC/ Y,) were tested for sensitivity to methotrexate (MIA) and trimetrexate, a second generation folate antagonist in clinical trials. Two of the three cell lines (A253 and SQCC/Y|) showed inherent resistance to methotrex ate, when cytotoxicity was evaluated after short term exposure (4 and 24 h). In contrast, all three cell lines were...

Osteosarcoma does not respond well to conventional dose methotrexate but does respond to high-dose methotrexate. Previous work has indicated that this resistance may be due to impaired transport of methotrexate across the cell membrane. In this study, the PT430 competitive displacement assay was adapted to evaluate methotrexate transport in 69 high-grade osteosarcoma tumor samples. All samples ...

Trimetrexate, a lipid-soluble analogue of methotrexate, appears to enter mammalian cells by passive diffusion, thus circumventing the methotrexate transport system which is frequently a subject for alterations leading to methotrexate resistance. Using a single-step selection protocol with trimetrexate, we have isolated 45 clonal variants and found the majority of them to be selectively resistan...