The herpes simplex virus thymidine kinase (HSV-TK) gene is being developed in the treatment of many different types of tumors. The HSV-TK gene sensitizes tumor cells to the antiviral drug ganciclovir (GCV) and mediates the bystander effect in which unmodified tumor cells are killed as well. Although this approach has shown a significant antitumor effect, the need to potentiate this therapy exists. The results of this study indicate that recombinant interferon alpha2a (1FNalpha2a) acts synergistically with GCV to kill HSV-TK-expressing PA1 human ovarian tumor cells. Furthermore, it enhances the bystander killing of nearby unmodified tumor cells that do not express the HSV-TK gene. Previous studies have suggested that in vitro and in vivo bystander effects may be mediated by different mechanisms. However, IFNalpha2a enhanced bystander killing in both systems, with the survival of mice bearing preexisting tumors being significantly prolonged when they were treated with IFNalpha2a and HSV-TK/GCV compared with either treatment alone. Mechanism studies have shown that treatment with IFNalpha2a and GCV caused an increase in cells in S phase 24 hours after therapy in the HSV-TK-expressing cells, but the mechanism of action of IFNalpha2a does not seem to be related to an increase in DNA damage, because GCV incorporation was not increased after treatment with IFNalpha2a. These findings suggest that IFNalpha2a may be a useful adjunctive therapy for the HSV-TK/GCV system.

Animals↗

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A therapeutic monitoring assay for N-methylformamide in human serum and urine.

This report describes a gas chromatographic procedure using a packed column and a flame ionization detector, which is suitable for the therapeutic monitoring of N-methylformamide (N-MF). N-MF is a polar compound that induces cancer cell maturation in vitro and exhibits antitumor activity with human tumors xenografted in nude mice. Toxicology studies with mice have shown this compound to be hepatotoxic. N-MF is currently undergoing Phase I clinical trial as an anticancer drug at this institution. In concert with its clinical trial, a method for the analysis of N-MF in biological fluids has been developed to study its pharmacokinetics. This method involves direct injection of urine or acetone-deproteinized serum onto a Chromosorb 103 column, using N,N-diethylformamide as an internal standard.

Chromatography, Gas↗

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Tissue analysis of N-methylformamide: organ distribution.

This report describes a gas chromatographic procedure, utilizing a packed column and flame ionization detector, suitable for the quantitative measurement of N-methylformamide (N-MF) in tissue samples. N-MF is a polar solvent that induces the maturation of cancer cells in vitro and, in vivo, exhibits antitumor activity with human tumors xenografted in nude (athymic) mice. Therapeutic monitoring is essential as toxicology studies have shown this compound to be hepatotoxic. N-MF is currently undergoing phase 1 clinical trials as an anticancer drug. This method of tissue analysis was developed to aid in the understanding of N-MF disposition and distribution in a murine model. The data thus generated may help predict the clinical behavior of this drug.

Animals↗

PubMedDate not supplied

Phyto-oestrogens in the prophylaxis of menstrual migraine.

BACKGROUND: Falling levels of estrogen is the major provocative factor in migraine associated with menstruation. OBJECTIVE: We assessed the efficacy of the combination of two phyto-oestrogens, as perimenstrual, prophylactic treatment of menstrual migraine and tested their effect on cerebral haemodynamic. SUBJECTS AND METHODS: Women with a history of menstrual migraine (i.e., attacks occurring exclusively on day 1+/-2 days of menstruation and at no other time of the cycle) were included in the study. Eleven women fulfilling the inclusion criteria underwent to a 3-month cyclic treatment with 56 mg of genisteine and 20 mg of diadzeine per day. Transcranial doppler evaluation (TCD) was performed at baseline and after treatment. RESULTS: Among the ten women who completed the study the average number of days with migraine during the baseline period decreased significantly after 3 months of therapy (P < 0.005). There were no major side-effects. Therapy did not affect cerebral blood flow velocities. CONCLUSIONS: Phyto-oestrogens appear to be an effective treatment in menstrual migraine prophylaxis. This effect seems to be unrelated to cerebral hemodynamic. Placebo-controlled trials on larger number of patients are necessary to confirm our findings.

Adult↗

PubMedDate not supplied

Possible cellular mechanism accounting for the cell type-specific vulnerability in Huntington's disease.

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Calcium Channels↗

PubMedDate not supplied

Electrophysiological evidence for the presence of ionotropic and metabotropic excitatory amino acid receptors on dopaminergic neurons of the rat mesencephalon: an in vitro study.

The actions of the ionotropic and metabotropic excitatory amino acid agonists AMPA, quisqualate, kainate, NMDA and trans-ACDP were studied by means of intracellular electrophysiological recordings from dopaminergic neurons of rat mesencephalon in brain slices. It was observed that all these agents evoked an inward current in cells which were voltage-clamped near the resting potential (-50, -60 mV). The membrane responses produced by AMPA, kainate and quisqualate were associated with an increase of the apparent input conductance while the responses induced by NMDA and trans-ACDP were associated with a decrease in the apparent input conductance. Therefore, stimulation of ionotropic and metabotropic amino acid receptors activates inward currents in the dopaminergic cells by different mechanisms.

Animals↗