Abstract A144: TriN 2755: Antitumor activity of a new cytotoxic therapeutic of the triazene class

Abstract

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.

Safety, tolerability and pharmacokinetic properties of the novel triazene TriN 2755 in tumour bearing dogs – a phase I study†

“…Although TriN 2755 belongs to the group of triazene compounds, it differs due to its physicochemical properties as well as its potent antineoplastic activity. TriN 2755 is highly photostable and hydrophylic, showing potent dose dependent antitumour activity in a variety of human cancer xenografts in murine models . Specifically, in these studies melanoma MEXF 462, colon adenocarcinoma CXF 280 and mammary MAXF 401 tumour models experienced a long lasting therapeutic effect and at the end of these studies most tumours were either in partial remission or in complete remission .…”

“…TriN 2755 is highly photostable and hydrophylic, showing potent dose dependent antitumour activity in a variety of human cancer xenografts in murine models . Specifically, in these studies melanoma MEXF 462, colon adenocarcinoma CXF 280 and mammary MAXF 401 tumour models experienced a long lasting therapeutic effect and at the end of these studies most tumours were either in partial remission or in complete remission . In addition, TriN 2755 was more effective than TMZ in melanoma MEXF 462 murine models, which was tested in parallel .…”

“…Specifically, in these studies melanoma MEXF 462, colon adenocarcinoma CXF 280 and mammary MAXF 401 tumour models experienced a long lasting therapeutic effect and at the end of these studies most tumours were either in partial remission or in complete remission . In addition, TriN 2755 was more effective than TMZ in melanoma MEXF 462 murine models, which was tested in parallel . The effects of TriN 2755 were also tested in DTIC resistant melanoma MEXF276 and MEXF1341 xenografted mice.…”