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Ftorafur

Ftorafur

Invention Nr. B 2218 USSR (1967)

Authors:


In the 50-ties chemotherapy was introduced in the treatment of malignant tumours besides the surgical treatment and radiation therapy. Scientists all over the world were searching for the possibilities to create low toxic anticancer preparations that wouldn’t cause any undesirable side effects. At that time a preparation 5-fluorouracyl had already been developed in Switzerland that selectively affected the cancer of gastrointestinal tract and lactealglands but was very toxic. Therefore its nucleoside analogue – 5-fluorouracyl-2'- deoxyriboside (FUDR) - was synthesized. Though it proved less toxic than 5-fluorouacyl and sufficiently effective as antitumour drug, its synthesis was too complicated and the drug was liable to such rapid decomposition in the organism that its application was hardly expedient.

In 1962 academician S.Hillers conceived the idea of searching for a new low toxic derivative of 5-fluorouracyl among the analogues of FUDR that could be characterized by greater stability with respect to the action of nucleoside phosphorylases. It was decided to substitute the deoxyribose residue by tetrahydrofuran residue in the FUDR molecule for this purpose. In 1964 testing of nucleoside deoxyanalogue synthesis and biological testing was begun in the Institute of Organic Synthesis (M. Lidaka, R. Zhuk, A. Zidermane). R.Zhuk was the first one to obtain and develop the synthesis method of 1-(2-tetrahydrofuryl)-5-fluorouracyl (that later gained the name of “Ftorafur” ).

Chronology of Ftorafur development


December,1964 First chemical synthesis of Ftorafur, Institute of Organic Synthesis
1965 – 1966 Experimental study, Biological Trials Department of the Institute
1967 Authorship certificate for Ftorafur (filed at the Committee for Inventions and Discoveries, USSR Council of Ministers)
1966 – 1967 Development of process technology, Experimental Plant of the Institute
1966 – 1969 Clinical testing of Ftorafur
1969 First foreign patent granted
1969 Authorization by Pharmacological Committee of the USSR Ministry of Health for the extensive use of Ftorafur to treat gastrointestinal tract tumours
1969 Beginning of cooperation with Japanese companies “Iskra” and “Tasho”
1972 – 1974 Studies of Ftorafur effectiveness in the treatment of breast cancer (authorized by Pharmacological Committee of the USSR Ministry of Health in 1974),
1975 – 1977 Studies of the effectiveness of capsulated Ftorafur oral administration (approved by Pharmacological Committee in 1977)
1976 Licence agreement and contract with American company “Bristol Myers”
1977 Starting of a new shop for Ftorafur manufacturing at the Institute’s Experimental Plant
1978 Beginning of clinical testing of lyophilized sodium salt of Ftorafur for the intravenous injections
1979 Starting of Ftorafur effectiveness studies in several skin diseases
September 1, 1979 Ftorafur is allowed to be used in a clinical practice in 15 different countries of the world

 

The clinical testing of Ftorafur was simultaneously carried out in 26 clinics of USSR and Latvia. The findings revealed that the preparation has a high anticancer activity and low toxicity and that it doesn’t influence the system of blood creation. One of the main ways of its impact is its transformation into 5- fluorouracyl under the influence of enzymes. Later also other analogues of 5-fluoroucyl were synthesized. The research on their physico-chemical properties allowed clarifying the interconnection between the structure and the biological activity of these compounds.

Utilization

Ftorafur is used for the treatment of alimentary canal tumours as well as for the treatment of breast cancer, several forms of ovary and brain tumours and liver cancer; it is used in combination with other chemical anticancer preparations, in combination with the surgical method and ray therapy. It allows to prolong the length of a lifetime of the operated cancer patients, averts the possibility of metastasis formation. It is still produced (under different names the most popular of which is “Tegaur” ) by more than 30 pharmaceutical companies in Japan, America and other countries of the world and by “Grindex” in Latvia that has been producing and exporting it for more than 25 years.