IDN 5390: A NEW TAXANE MOLECULE FOR A MORE TOLERABLE CHEMIOTHERAPY
Pre-clinical tests have shown that a new taxane skeleton molecule, IDN 5390, presents low toxicity, a selective activity in angiogenesis and can be administered orally. Due to its anti-angiogenetic and anti-metastatic properties, the new seco-derivative can be considered the prototype of a new class of antitumoral molecules modified and derived from the yew tree. The antitumoral activity of IDN 5390 has been confirmed in a variety of human tumor xenografts, including ovarian and colon carcinoma and glioblastoma. IDN 5390 showed to be able to target class III beta-tubulin overcoming paclitaxel resistance. Its bioavailability and pharmacokinetic profile were presented at the 16th EORTC-NCI-AACR. "The results we have achieved thus far are promising", explains Ezio Bombardelli, President of Indena's Scientific Board. He added this novel compound of vegetable origin could provide patients with a more tolerable form of chemotherapy treatment - less invasive and more efficient.
NEW TAXANES SUBSTITUTED IN POSITION 14: FOLLOW-UP OF IDN 5109
The collaboration of Indena with the Institute of Organic Chemistry and Fotoreactivity (ISOF) of the CNR in Bologna and the "Alessandro Marchesini" Institute of Organic Chemistry of the University of Milan, brought to the identification of new taxanes with promising preclinical profile. The compounds, bearing original funcionalities in position 14, are ideally follow-up of IDN5109, already in phase II clinical trials. The result of the research represents a milestone not only from a pharmacological point of view, but also from a clinical point, since the modification of position 14 always represented a challenge to all the scientists. GLUCOSINOLATES\MYROSINASE SYSTEM TO OVERCOME CISPLATIN RESISTANCE
This new line of research focuses on the specific active principles extracted from broccoli and other vegetables in the Brassica family. It has long been known that these vegetables possess properties important in preventing certain forms of cancer, lowering the risk of cataract, and reducing the effects of a stroke. Only recently however has it been discovered that certain molecules contained in broccoli, the isiothiocyanates deriving from the enzymatic transformation of glucosinolates, directly inhibit cell growth, inducing the phenomena of programmed cell death (apoptosis). Moreover, exploiting the capacity of the isiothiocyanates to stimulate cells in the production and activation of the detoxifying enzymes, studies have been made to explore the possibility that this mechanism is able to contrast the insurgence of pharmacological resistance, especially in the case of chemotherapy using cisplatin. Indena’s pre-clinical research has therefore shown that the use of glucosinolates/isiothiocyanates could offer a considerable therapeutic advantage in overcoming resistance to radio and chemo therapy. This study was carried out in conjunction with the Bologna Research Institute for Industrial Crops and Rome’s Catholic University of the Sacred Heart 14-FUNCTIONALIZED TAXANES
A new line of research in which Indena is involved follows the route of ortataxel, an analogue of active paclitaxel taken orally and less subject to resistance. This derivate of 14-hydroxy-baccatin, at present in clinical phase II, is quite promising and it has stimulated a search for new analogues with better chemical-physical features and anti-tumour action. A series of synthetic molecules, object of this study, has shown interesting potential on breast tumors. This study was carried out in collaboration with the Roswell Park Cancer Institute in Buffalo (NY), the Institute of Organic Chemistry and Fotoreactivity (ISOF) of the CNR in Bologna and the A. Marchesini Institute of Organic Chemistry in Milan.
PACLITAXEL-RESISTANCE IN ADVANCED OVARIAN CANCER
Indena is interested in sponsoring translational research from the laboratory to the clinic. It has been shown that there is an increase in the beta tubulin isotype III (TUBB4) in tumors that resist paclitaxel therapy. Beta tubulin is the classical target of this class of compounds. Since TUBB4 expression is low in non-tumoral ovarian tissue, it could be an important target in developing new anti-tumoral agents that can overcome taxane resistance. This study was carried out at the Gemelli Hospital in Rome and the Catholic University of the Sacred Heart in Campobasso. IDN 5491: PROMISING RESULTS FROM A NEW ANTIDEPRESSANT DRUG
Hyperforin has been reported to be strongly involved in the pharmacological and clinical antidepressant activity of Hypericum perforatum L.
Hyperforin, as such, never got proposal for drug development due to its high chemical instability. Indena synthesized a new hyperforin derivative named IDN 5491, which has been selected as the most interesting candidate for pharmaceutical development among a wide number of compounds screened.
Several preclinical pharmacological tests, performed in vitro and in vivo, demonstrated the great potential of IDN 5491 as an antidepressant agent endowed with a peculiar mechanism of action.
The compound is well tolerated in preliminary toxicological studies. IdB 1016: THE BIOAVAILABLE FLAVONOID SILIPIDE, A NEW CHALLENGE IN ONCOLOGICAL FIELD
IdB 1016 (Silipide) is a complex between silybin and phosphatidylcholine with improved bioavailability and after oral administration, it gives plasma levels significantly higher than those found after the administration of silybin or silymarin to rats or to humans. IdB 1016 has been previously investigated as a therapeutic agent for the treatment of acute and chronic viral or toxic hepatitis. Clinical investigations of efficacy of IdB 1016 on hepatic diseases ended in 1995 due to change in strategic pipeline development of the company.
A new therapeutic use for this compound is under investigation. In animal models, IdB 1016 administered with a prolonged schedule showed a significant antitumor activity against human ovarian cancer xenografted into athymic mice. In addition, in the latter animal model, IdB 1016 was also shown to potentiate the activity of optimal or sub-optimal doses of cisplatin.
The drug is very well tolerated in acute, sub acute, and chronic toxicity studies. IdB 1016 did not show any effect in reproduction toxicity studies and showed no mutagenic effects in several test systems. The good tolerability of the product has been confirmed in Phase I clinical studies, following repeated administration of dosages up to 2.8 g/day to healthy volunteers.
Given the antitumor activity and the favorable toxicity profile, a phase II non-randomised clinical study is now ongoing to evaluate the efficacy of daily administration of IdB 1016 in the serological recurrence of disease in ovarian cancer patients without valuable lesions. |
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