When the solution comes from the sea: PharmaMar, world leader in marine biotechnology against cancer.

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“In total, it is estimated that between a 0,4% and a 1,8% of the natural extracts from the organic matter (belonging to terrestrial plants and marine animals, respectively) could contain antitumoural active principles.” Cragg GM et al (1994).

 

The first company in the history to develop and market a medicine with marine origin was the biopharmaceutical Pharmamar, spanish company that also  is currently world leader into the discovery of new antitumoural drugs originated from this overflowing source of active principles.    

 

And that is that seas and oceans cover the 70% of the world and host to 95% of the living creatures. It was to be hoped, according to data from the National Cancer Institute, that the rate of active extracts from marine origin were really higher than the terrestrial.  

Do you want to know how they develop the stages of this so peculiar Drug Discover ? discover it below. 

 

Marine species from the coral barrier. Source pixabay.
 
Ecteinascidia turbinata tunicate colony and ET-743 structure, Yondelis active principle. 

Currently, the company counts on with the world´s major collection of marine organisms, approximately 200.000 samples among macroorganisms and microorganisms,  and develops and markets in Europe the antitumoural YONDELIS® (trabectedina), discovered in a Ecteinascidia turbinata tunicate colony, and that now they produce it synthetically.  

Watching the biological activity of the incredible variety of substances that have been developed by the marine organisms, these represent their mechanism to respond the vital needs such as the survival, the defence, the attack and the communication, and that represent clear sources of strategies to confront infinity of diseases.    

 

“If we observe two sponges competing for a substratum of fixing, or the employment of chemical defenses in immobile beings not to be preyed, we will realize that the evolutionary strategy has provided them with substances capable of stopping the growth of the rivals and it can be applied to the cancer, where the cellular division plays a determinant role.” Fernando de la Calle, Chief of the Department of Microbiology in PharmaMar. 

 

Yondelis action mechanism. It actions inhibiting the RNA pol II, thus avoiding transcriptional hiperactive cancer cells to overexpress their tumoral factors. 

YONDELIS® is indicated in the treatment of Soft-Tissue Sarcoma and Relapsed Ovarian Cancer in combination with  DOXIL®/CAELYX® (doxorubicin HCl liposome injection). It has a unique mechanism of action based on interaction with the minor groove of deoxyribonucleic acid (DNA), bending the helix to the major groove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and DNA repair pathways, resulting in perturbation of the cell cycle.

Namely is a selective inhibitor of trans-activated RNA polymerase II transcription. It selectively block the elongation phase of messenger RNA synthesis performed by RNA polymerase II. However, it do not inhibit RNA polymerase I or mitochondrial RNA polymerase, nor do it affect basal transcription: its action mechanism very selectively inhibits RNA polymerase II transcription, concerning of selective form the tumour cells that are hyperactive to transcripcional level.

It is the first medicament of marine origin approved in Europe for these indications, is available in almost 80 countries and present on the principal oncology markets: The United States, Europe and Japan. 

Market expansion of the Yondelis antitumoral.

 

In addition PharmaMar arranges of an important preclinic portfolio of compounds and a powerful program of research and development, which turns it into an integrated biophamacy, realizing all the activities that include the Drug Discovery

1. Beginning for the search of marine organisms across its expeditions department. This team is formed by marine biologists and professional divers, pioneer in the exploration of the marine biodiversity, managing to reach depths of up to 120 meters. 

They collect by hand only a few grams of every organism, both micro- and macroorganisms, in different locations along the world during the year, for what they cause impact neither on the natural environment nor the biodiversity.

 

Submarine expedition of the PharmaMar divers team. 

 

2. Synthesis Development. In macroorganisms it begins with the crude extraction of the major possible quantity of compounds that contains every sample. Then  becomes a screening to verify the antitumoral activity of each one compound into different cellular lines of cancer: breast, lung, colon and pancreas. On having found active specific principles in every tissue it is continued by its purification process by HPLC.

Bacteria culture. Source Pixabay.

In marine microorganisms first is performed a process of isolation and characterization of the miles of different bacteria that they find in the marine environment. Later the isolated species are cultivated and an extraction in crude is done to get from them their metabolites, in which their antitumoral activity is tested again in cellular lines of cancer.

To the most interesting bacteria to produce active metabolites there is realized the raise of their culturing, first in interaction flasks and later in fermenters of major capacity. By this way they obtain the necessary quantity of active metabolites to continue with the investigation and to develop the necessary compounds to begin with the clinical essays.

Regarding to the molecular structure of the new active compounds, this one is obtained by RMN (Nuclear Magnetic Resonance), and later is proceeded to heir production by chemical synthesis.

Vial with the Drug formulation.

3. Compounds formulation.  Thera are prepared vials with the exact quantity of the active substance by freeze drying, obtaining a stable and solid compound, which represents their final form, list to be stored or transported.

4. Clinical essays. They begin with proof of concept non-clinical essays in animals, and tissue and body liquids samples, like plasma, urine, tumoral tissues, etc, in which it is checked the in vivo activity of the metabolites.

This stage allows to detect the best way of administering the compounds, of reaching the maximum level of efficiency, and to reduce everything possible the toxicity. 

5. Marketing.

 

All these steps allow the development of the stages from the Drug Discovery to the Drug Development.

 

PharmaMar Drug Discovery way.

 

In this video you can know every one of the steps that are performed into these processes by the Biopharmacist, guided by the hand of Simon Munt, Chief of the Medical Chemistry Department of PharmaMar. The images from the submarine explorations and the aquatic biodiversity are exciting!

 

 

“The nature has distributed medicines thorughout.” Plinio the old.74 b.C.

 

And it is that the seas and the oceans are the big fountains of the biodiversity, in them there is a whole drugstore performed by million years of evolution, and until a few decades within reach of our hands. The organization of marine expeditions in different locations of the world, the collection of samples, the creation of a library of organisms and the search and development of medicaments from them is the great task that must undertake any organization that wants to reach this goal.

 

Up to what depth would you dive to obtain it?

 

* To accede to the clinical essays developed with Trabedectina it is possible to obtain information across clinicaltrials.gov and clinicaltrialsregister.eu.

 

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