Injection of the peptide cyclo(Leu-Gly) into rats prior to chronic exposure to morphine, inhibits: 1) the development of analgesic tolerance; 2) some signs of physical dependence; and, 3) morphine-induced increases in behavioral responses to dopamine agonists. Although there was no change in the total number of high affinity striatal dopamine receptors, chronic morphine treatment did increase the affinity of the ligand at the receptor. The peptide blocked not only the affinity change, but the increased behavioral response to apomorphine as well. These behavioral changes correlate significantly with the neurochemical changes in dopamine receptors following chronic morphine treatment. Therefore, some of the pharmacological efforts of morphine may be mediated by changes in CNS dopamine receptors and that the peptides may act by inhibiting these neurochemical changes.

Analgesia↗

PubMedDate not supplied

Cyclo(Leu-Gly) has opposite effects on D-2 dopamine receptors in different brain areas.

Cyclo(Leu-Gly) (cLG), a diketopiperazine analog of Pro-Leu-Gly-NH2 (MIF), affects a number of physiological and behavioral responses to the endogenous neurotransmitter, dopamine (DA). In the present series of experiments, the effect of in vivo administration of cLG (8 mg/kg) was investigated five days following subcutaneous administration. It was found that cLG administration of cLG (8 mg/kg) was investigated five days following subcutaneous administration. It was found that cLG administration caused a supersensitive behavioral response, measured by increased stereotypic sniffing, to the DA agonist, apomorphine (APO). At the same time, an increase was found in the affinity for dopamine (DA), as measured by dopamine inhibition of 3H-spiroperidol binding to D-2 DA receptors in striatum (nigro-striatal DA tract). In contrast, the same peptide treatment caused a subsensitive physiological response to APO-induced hypothermia, concomitant with a decrease in affinity for dopamine, as measured by DA inhibition of 3H-spiroperidol binding to D-2 DA receptors in hypothalamus (incerto-hypothalamic DA tract). These results suggest that a single neuromodulatory agent, the peptide cLG, can elicit diametrically opposite effects on D-2 DA receptors and on the corresponding physiological endpoints in two different brain areas.

Animals↗

PubMedDate not supplied

A radical perspective on ulcerative colitis.

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Antioxidants↗

PubMedDate not supplied

Development of cross-resistance to tamoxifen in raloxifene-treated breast carcinoma cells.

Selective estrogen receptor modifiers (SERMs) are used chronically in the treatment of breast cancer and osteoporosis but some patients become resistant, at which point second-line SERMs are considered as options. Because the use of SERMs is increasing and breast cancer is so common, we tested the hypothesis that treatment with SERMs can induce cross-resistance to other SERMs. We used three cultured breast carcinoma cell lines (MCF-7, ZR-75-1, and T47D) which are estrogen-receptor-positive (ER+) and are prone to developing resistance to hormonal treatment. Cell lines were exposed to increasing doses of raloxifene. Raloxifene-resistant clones were selected and tested for cross-resistance to tamoxifen. Compared to untreated cells, raloxifene-resistant clones showed an increased IC50 (reduced potency) of about 15,000-fold with no apparent change in maximal inhibition of cell growth. These same raloxifene-resistant clones were also about 15-fold more resistant to the growth-inhibiting effects of tamoxifen. While the resistance to tamoxifen is considerably less marked (1000-fold less), it is large enough to raise the question as to whether patients who become resistant to raloxifene will benefit by switching to tamoxifen or vice versa.

Antineoplastic Agents, Hormonal↗

PubMedDate not supplied

Co-transfection of MDR1 and MRP antisense RNAs abolishes the drug resistance in multidrug-resistant human lung cancer cells.

The resistance of lung cancer cells to the therapeutic actions of anticancer drugs is a serious clinical problem often encountered during cancer chemotherapy. It is very important, therefore, to investigate how to prevent and/or reverse this drug resistance. To this end, we took advantage of the fact that the overexpression of MDR1 and MRP genes, two genes known to be associated with the development of drug resistance, is very common in lung cancer. We used antisense RNA in an attempt to prevent expression of the protein products of these genes. Using a retrovirus, we introduced the antisense RNAs of MDR1 and MRP genes into doxorubicin-selected, multidrug-resistant GAOK cells, a cell which overexpresses both MDR1 and MRP genes. The expression levels of the products of the MDR1 gene (Pgp) and MRP gene (Mrp) in the transfected cells were analyzed using flow cytometry, and the drug resistances of the transfected cells were detected by a cell viability (MTT) assay. The expression of Pgp and Mrp in the transfected cells was almost completely inhibited by the antisense RNAs: expression levels decreased 64% and 93%, respectively. In parallel, the drug resistance of these cells decreased about 99% to doxorubicin, 98% to vinblastine, and 97% to colchicine. These results show that: a) antisense RNAs can attenuate drug resistance, an inhibition that might lead to new treatments for patients who are, or become, refractory to conventional chemotherapy; b) MDR1 and MRP appear to be cooperating to confer drug resistance in GAOK cells.

3T3 Cells↗