Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas.

Drug treatment of malignant gliomas is limited by the intrinsic resistance of glioma stem cells (GSCs) to chemotherapy. GSCs isolated from human glioblastoma multiforme (GBM) expressed metabotropic glutamate receptors (mGlu3 receptors). The DNA-alkylating agent, temozolomide, killed GSCs only if mGlu3 receptors were knocked down or pharmacologically inhibited. In contrast, mGlu3 receptor blockade did not affect the action of paclitaxel, etoposide, cis-platinum, and irinotecan. mGlu3 receptor blockade enabled temozolomide toxicity by inhibiting a phosphatidylinositol-3-kinase/nuclear factor-κB pathway that supports the expression of O(6)-methylguanine-DNA methyltransferase (MGMT), an enzyme that confers resistance against DNA-alkylating agents. In mice implanted with GSCs into the brain, temozolomide combined with mGlu3 receptor blockade substantially reduced tumor growth. Finally, 87 patients with GBM undergoing surgery followed by adjuvant chemotherapy with temozolomide survived for longer time if tumor cells expressed low levels of mGlu3 receptors. In addition, the methylation state of the MGMT gene promoter in tumor extracts influenced survival only in those patients with low expression of mGlu3 receptors in the tumor. These data encourage the use of mGlu3 receptor antagonists as add-on drugs in the treatment of GBM, and suggest that the transcript of mGlu3 receptors should be measured in tumor specimens for a correct prediction of patients' survival in response to temozolomide treatment.

Activation of mGlu2/3 metabotropic glutamate receptors negatively regulates the stimulation of inositol phospholipid hydrolysis mediated by 5-hydroxytryptamine2A serotonin receptors in the frontal cortex of living mice.

The interaction between 5-hydroxytryptamine(2A) (5-HT(2A)) serotonin receptors and metabotropic glutamate (mGlu) 2/3 receptors underlies the antipsychotic activity of mGlu2/3 receptor agonists in experimental animals and humans. The molecular nature of this interaction is only partially known. We here report for the first time that pharmacological activation of mGlu2/3 receptors attenuates the stimulation of polyphosphoinositide (PI) hydrolysis mediated by 5-HT(2A) receptors in the frontal cortex of living mice. Mice were injected intracerebroventricularly with [myo-(3)H]inositol and treated with drugs 1 h after a pretreatment with lithium, which blocks the conversion of inositol monophosphate into free inositol. Systemic injection of the mGlu2/3 receptor agonist (-)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) inhibited the stimulation of PI hydrolysis induced by the hallucinogenic 5-HT(2A) receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) without affecting the stimulation by mGlu1/5 or muscarinic receptors. The action of LY379268 was prevented by the preferential mGlu2/3 receptor antagonist (2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycyclopropyl)glycine (LY341495). N-(4'-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), a selective mGlu2 receptor enhancer, also reduced DOI-stimulated PI hydrolysis when combined with subthreshold doses of LY379268. Systemic LY379268 inhibited DOI-stimulated PI hydrolysis in mice lacking either mGlu2 or mGlu3 receptors but was inactive in double mGlu2/mGlu3 receptor knockout mice, suggesting that both mGlu2 and mGlu3 receptors interact with 5-HT(2A) receptors. Surprisingly, contrasting results were obtained in cortical slice preparations, where LY379268 amplified both DOI- and 3,5-dihydroxyphenylglycine-stimulated PI hydrolysis. Amplification was abrogated by the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine, suggesting that experiments in brain slices are biased by an additional component of receptor-stimulated PI hydrolysis. This highlights the importance of in vivo models for the study of the interaction between 5-HT(2A) and mGlu2/3 receptors.

Antimicrobial prophylaxis for transrectal prostatic biopsy: a prospective study of ciprofloxacin vs piperacillin/tazobactam.

OBJECTIVE: To compare the efficacy of short-term parenteral prophylaxis with piperacillin/tazobactam (P/T) with long-term oral prophylaxis with ciprofloxacin in preventing infective complications after transrectal prostatic biopsy (TPB). PATIENTS AND METHODS: Patients scheduled for TPB were randomized to receive P/T (2250 mg intramuscular) twice daily for 2 days (Group 1), or ciprofloxacin (500 mg orally) twice daily for 7 days (Group 2), beginning on the evening before the procedure in both groups. All patients received a 100-mL phosphate enema 3 h before TPB. Evaluation included self-recording of body temperature in the 3 days after TPB, and culture of mid-stream urine (MSU) samples taken before and 3 and 15 days after TPB. Patients with indwelling urethral catheters or taking antibiotics or immunosuppressive drugs were excluded, as were patients with positive MSU cultures before TPB. RESULTS: Of the 138 evaluable patients, 72 received parenteral P/T and 66 oral ciprofloxacin. Bacteriuria (> 105 c.f.u./mL) after TPB occurred in two of 72 (2.8%) patients in Group 1 and in three of 66 (4.5%) patients in Group 2; this difference was not statistically significant (P > 0.1). However, of the five patients with bacteriuria, two were symptomatic and both were in Group 2. Pyrexia occurred in only one patient in Group 2 with symptomatic urinary tract infection, and required hospitalization. No other patient reported a body temperature openface> 37.5 degrees C or drug-related side-effects. CONCLUSIONS: This prospective study showed that short-term prophylaxis with P/T was associated with a low rate of asymptomatic bacteriuria, requiring no further treatment, whereas although the rate was similar on long-term prophylaxis with ciprofloxacin patients required further treatment, with one needing hospitalization. We recommend short-term prophylaxis with P/T despite its disadvantages of cost and parenteral administration.