Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6J mice.

RATIONALE: Knockout and transgenic mice provide a tool for assessing the mechanisms of action of antidepressants. The effectiveness of oral administration of the tricyclic antidepressant amitriptyline (AMI) was assessed in C57BL/6J (B6) mice, a common genetic background on which knockout and transgenic mice are maintained. OBJECTIVES: We determined whether oral AMI would have antidepressant-like effects in B6 mice and whether these effects varied according to sex, duration of treatment, and the depression model utilized. METHODS: Male and female B6 mice were administered AMI (200 microg/ml) in the drinking water as the sole source of fluid, along with 2% saccharin to increase palatability. Control mice were administered 2% saccharin alone. Mice were assessed for responsiveness to AMI in the tail suspension test (TST), the forced swim test (FST), and the learned helplessness (LH) paradigm. RESULTS: In the TST, AMI decreased immobility time regardless of sex or duration of treatment. AMI also decreased immobility time in the FST, but chronic treatment was necessary for full efficacy in both sexes. In the LH paradigm, both subchronic and chronic AMI treatment decreased escape latencies in female mice, but AMI was effective only after chronic treatment in males. The antidepressant-like effects of AMI could not be explained by differences in locomotor activity because activity levels were not altered by antidepressant treatment. CONCLUSIONS: Overall, oral AMI administration provides a valid model for behavioral assessment of antidepressant-like effects in knockout and transgenic mice maintained on a B6 background, but the effectiveness of oral AMI varies depending on sex, duration of treatment, and the depression model used.

Ionizing radiation does not alter the antitumor activity of herpes simplex virus vector G207 in subcutaneous tumor models of human and murine prostate cancer.

Viral gene therapy against malignant tumors holds great promise for tumors that are susceptible to the oncolytic activity of viruses. One advantage of oncolytic viral therapy is that it can potentially be combined with other therapies, such as radiotherapy, to obtain an enhanced tumor response. In the case of prostate cancer, herpes simplex virus-mediated therapies have been shown to be highly effective in animal models; however, studies of the efficacy of combined viral and radiation therapy have not yet been reported. In this study, we have combined G207, a multimutated HSV type 1 vector, with external beam radiation therapy of prostate tumors grown subcutaneously in mice. We examined both the human LNCaP tumor in athymic mice and the mouse transgenic TRAMP tumor in either athymic mice or its syngeneic host, C57BL/6 mice. Virus was delivered either intravenously, in the case of LNCaP, or intratumorally, in the case of TRAMP. We found that individually, either G207 or radiation was effective in delaying tumor growth in these models. However, delivering the treatments simultaneously did not produce an enhanced effect.

p21WAF1/CIP1 antisense therapy radiosensitizes human colon cancer by converting growth arrest to apoptosis.

Substantial evidence suggests that loss of cellular p21WAF1/CIP1 results in increased apoptotic killing by ionizing radiation. We hypothesized that a p21 antisense (AS) oligodeoxynucleotide (ODN) could be used to sensitize cancer cells to radiotherapy. In vitro treatment of colon cancer cells (HCT116/p21+/+) with p21 AS ODN (200 nM) led to inhibition of radiation-induced p21 expression (>95% inhibition, 0-30 Gy), resulting in a loss of G1 arrest and an enhancement of apoptosis to comparable levels and with similar kinetics to HCT116/p21-/- cells (approximately 60% apoptotic cells at 96 h after 10 Gy). In vivo, p21 AS ODN in combination with radiation (i.p. ODN for 6 days at 20 mg/kg/day and 15 Gy) increased apoptosis in s.c. p21+/+ tumors in nude mice to levels similar to those of p21-/- tumors (2-fold at 24 h postirradiation) and improved radiocurability of p21+/+ tumors to levels comparable to those of p21-/- tumors (p21+/+, two of eight cures versus p21-/-, two of nine cures). Our findings suggest that p21 AS treatment may be a rational approach to improve conventional radiotherapy outcomes.