Reversal of Multidrug Resistance by Lipophilic Drugs1
The phenomenon of multidrug resistance implies that a wide spectrum of structurally and functionally unrelated chemotherapeutic drugs are recognized and processed by the molecular system which protects multidrug-resistant (MDR) cells against lipophilic cytotoxic drugs. This suggests that lipophilic agents with low toxicity may also be recognized and processed by this molecular system. At high concentrations these agents might saturate the system, thereby reversing multidrug resistance. In support of this hypothesis, 19 (73%) of 26 arbitrarily chosen lipophilic drugs were in this study found to increase the accumulation of actinomycin D in MDR \\ I III 164 cells. The most potent of these drugs were also shown to sensitize these cells to the cytotoxic effect of actinomycin D and doxorubicin. There was a good correlation between the ability of the lipophilic drugs to induce an increased accumulation of actinomycin D in Ml>R cells and their ability to sensitize these cells to the cytotoxic effect of chemotherapeutic drugs. The ability to reverse drug resistance ap peared to be additive, since increased accumulation of actinomycin D was also obtained by combining low concentrations of various lipophilic drugs. This may be a way to reduce the in vivo toxic effect of the lipophilic drugs yet still obtain a reversal of drug resistance. When MDR cells were exposed to lipophilic drugs which reversed drug resistance, the synergistic cytotoxic effect of actinomycin D and tumor necrosis factor was obtained at reduced actinomycin D concentrations.
RNAi Induced Inhibition of MRP1 Expression and Reversal of Drug Resistance in Human Promyelocytic HL60 Cell Line
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...متن کامل
A phenotype conferring selective resistance to lipophilic antifolates in Chinese hamster ovary cells.
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...متن کامل
The multidrug-resistant P-glycoprotein (Pgp), a M(r) 170,000 plasma membrane protein encoded by the mammalian multidrug resistance gene (MDR1), appears to function as an energy-dependent efflux pump. Many of the drugs that interact with Pgp are lipophilic and cationic at physiological pH. We tested the hypothesis that the synthetic gamma-emitting organotechnetium complex, hexakis(2-methoxyisobu...متن کامل
Multidrug-resistant cells are thought to maintain low intracellular cytotoxic drug concentration though the active efflux of drugs across the cell membrane. It is presently believed that P-glycoprotein mediates this energy-dependent drug efflux by interacting directly with various lipophilic compounds. In this report, we have used [3H]azidopine in a photoaffinity labeling assay to study the eff...متن کامل
Multidrug resistance is a serious obstacle encountered in cancer treatment. Since drug resistance in human cancer is mainly associated with overexpression of the multidrug resistance gene 1 (MDR1), the promoter of the human MDR1 gene may be a target for multidrug resistance reversion drug screening. In the present study, HEK293T cells were transfected with pGL3 reporter plasmids containing the ...متن کامل