Fig. 4. Antitumor activity of ^-941. ^-941 induces a 60% decrease of primary tumor growth (DA3 model).
most representative (34,35). DA3 cells are murine mammary carcinoma cells obtained by the treatment of mouse 7,12-dimethylbenzanthracene (DMBA). Injected subcutane-ously into mice, the cells form a slow growing tumor with low metastatic potential. Mice injected with the DA3 cells received a daily oral administration of ^-941 or a saline solution for the control group 7 d following cell inoculation. Tumor growth was monitored every third day by determination of the relative tumor volume. The mice were sacrificed on d 54 after tumor inoculation. The tumors were then dissected and weighed. Oral administration of 100 mg/kg d of ^-941 as compared to the control group resulted in a statistically significant inhibition of 60% of tumor volume (p < 0.02) (Fig. 4) and of 47% of tumor weight (p < 0.01) (data not shown). Similar antitumor effects of ^-941 have also been observed in metastatic models, like the Lewis lung carcinoma.
The evolution of chronic inflammatory phenomena being tightly linked to the formation of new vessels, the anti-inflammatory activity of ^-941 has been tested in a human model of skin irritation (33). The degree of redness of the skin was measured with a chronometer and compared with a positive and a negative control. The value of the negative control was estimated as 100% of irritancy. The results showed that administration of ^-941 was efficient in reducing skin irritation in a dose-dependent manner (Fig. 5). Therefore, the above data are the first pharmacological demonstration that an orally administered cartilage extract is able to slow down the progression of a variety of pathological angiodependent situations. In addition, they demonstrate that, when given orally, the active component(s) of ^-941 is (are) bioavailable and nontoxic. The absence of toxicity has further been verified in different species. ^-941 was administered orally in mice, rats, dogs, and primates at various doses. Until now no toxic effects directly associated with ^-941 administration have been reported.
Because it has virtually no toxic effect, ^-941 has been engaged in phase I and phase II clinical trials in Canada and the United States for the treatment of breast, prostate, and lung carcinoma, as well as for psoriasis and age-related macular degeneration. Up to 430 cancer patients for more than 25 mo have to-date received a daily oral dose of ^-941. No serious adverse reactions associated with the use of ^-941 have been reported thus far. Most interestingly, preliminary data of clinical efficacy from lung and prostate cancer as c 75 O _
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