Herpes simplex virus type 1 (HSV-1) gene expression is concomitant with a selective shutoff of host protein synthesis. While the synthesis of the vast majority of cellular proteins is inhibited immediately after infection, several cellular proteins continue to be synthesized, even during the late phase of infection. Because these cellular proteins may intervene in the life cycle of the virus, we undertook two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) analyses to evaluate the proportion of cellular proteins that is represented by these particular proteins. Human cells were infected with HSV-1. At different times after infection, proteins were labeled with 35S just prior to harvesting. The rate of synthesis of a set of 183 acidic host proteins, as well as that of ribosomal proteins, was measured during the course of infection, after separation by 2-D PAGE. As expected, HSV-1 induces a strong inhibition of host protein synthesis immediately after infection. However, the synthesis of basic ribosomal proteins and that of an unexpected high proportion of the sub-set of cellular proteins analyzed is sustained or stimulated during HSV-1 infection. A 2-D PAGE analysis outlining the expression patterns of these proteins at different times of infection is presented.

Herpes simplex virus type 1 (HSV-1) gene expression is concomitant with a selective shutoff of host protein synthesis. While the synthesis of the vast majority of cellular proteins is inhibited immediately after infection, several cellular proteins continue to be synthesized, even during the late phase of infection. Because these cellular proteins may intervene in the life cycle of the virus, we undertook two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) analyses to evaluate the proportion of cellular proteins that is represented by these particular proteins. Human cells were infected with HSV-1. At different times after infection, proteins were labeled with 35S just prior to harvesting. The rate of synthesis of a set of 183 acidic host proteins, as well as that of ribosomal proteins, was measured during the course of infection, after separation by 2-D PAGE. As expected, HSV-1 induces a strong inhibition of host protein synthesis immediately after infection. However, the synthesis of basic ribosomal proteins and that of an unexpected high proportion of the sub-set of cellular proteins analyzed is sustained or stimulated during HSV-1 infection. A 2-D PAGE analysis outlining the expression patterns of these proteins at different times of infection is presented.

The new cytotoxic anti-neoplastic agent TriN 2755, containing a triazene unit with alkylating properties, has been tested in a variety of patient-derived tumor xenograft models. In these models, TriN 2755 displays potent in vivo anti-tumor activity. In rat, dog and mini pig toxicity studies, TriN 2755 demonstrated a favourable safety profile. Here, we present efficacy data in nude mice of TriN 2755 tested in 15 human tumor xenograft models derived from 9 histologies Oncotest has developed >200 patient-derived solid tumor models growing s.c. in nude mice. These human tumors were transplanted directly into mice in order to retain the malignant phenotypes as in the patient. Since tumor morphology and sensitivity to anti-cancer drugs is being preserved in these models, results are of high clinical relevance. A total of 15 xenograft models, among them 4 mammary, 3 melanoma, 2 prostate, 1 colon, pancreas, lung, head and neck, uterine body and bladder tumor models were tested. Tumor-bearing nude mice received TriN 2755 i.p. at doses of 300 to 540mg/kg and different treatment schedules. Treatment started when tumors had grown to diameters of 6–8 mm. Anti-tumor activity was assessed as tumor volume inhibition relative to a vehicle control group (T/C value in %). Tolerability was analysed by recording mortality and body weight loss. TriN 2755 is a promising anti-cancer agent with an average optimum T/C value of 29.7 % over the 15 experiments representing each tumor model. Optimum T/C values below 50 % were reached in 9/15 tumor models, borderline activity with optimum T/C between 50 and 65 % was observed in 4/15 xenografts with only 2 xenografts being resistant to TriN 2755 (optimum T/C value above 65 %). TriN 2755 had a long lasting therapeutic effect in the melanoma MEXF 462, colon adenocarcinoma CXF 280 and mammary MAXF 401 tumor models. On the last day of treatment, most tumors were either in partial or complete remission. This remission generally lasted until the end of the observation period (days 45, 56 and 42, respectively). TriN 2755 was more effective in these studies than standard-of-care drugs tested in parallel (5- Fluorouracil in colon cancer and Temozolomide in melanomas). Tolerability of TriN 2755 was good with a moderate mortality rate and body weight loss. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A144.

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