Great discoveries...

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Published on Sunday, 21 July 2013

Bullettino delle scienze medicheThe researchers at the La Sapienza University of Rome coordinated by Elio Ziparo - Department of Anatomical, Histological, Istituto Pasteur and Forensic & Orthopaedic Sciences (DAHFMO) Unit of Histology and Medical Embryology, La Sapienza University of Rome -, in collaboration with Professor Carlo Maria Croce, director of the Comprehensive Cancer Center in Cleveland (Ohio) - Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210 -, have discovered, forty years later than Prof. Luigi Di Bella, the antitumor activity of Retinoic Acid.

In 1949 (!) Prof. Luigi Di Bella assigned to one of his students of the Faculty of Pharmacy, Dr. Vigildo Ferrari, a thesis on Retinoic acid! Since then he utilized it, together with Vitamin E, in combination with the other 2 retinoids, β-Carotene and Axerophthol palmitate, in the prevention and treatment of tumors.

 

DiBella-Leukemia

7/Dec/1973!

DiBella-Leukemi...

Publications of Prof. Luigi Di Bella on retinoids date back to the 40's! In December 1973 Prof. Luigi Di Bella presented to the Medical and Surgical Society of Bologna a report on the use of the three retinoids (β-Carotene, Axerophthol palmitate, Retinoic Acid (ATRA), solubilized in Vitamin E which enhance their anti-tumor properties preventing oxidation and prolonging their half-life), together with Melatonin, in 7 cases of leukemia and thrombocytopenia (click on "DiBella-Leukemia" figure), e.g. Acute Lymphatic Leukemia.



The report was published the following year: Orientamenti fisiologici nella terapia delle emopatie (Fisiological guidelines in the therapy of hemopathy) - BULLETTINO DELLE SCIENZE MEDICHE - Organo della Società e Scuola Medica Chirurgica di Bologna - Anno CXLV - Fasc. I - 1974:


 

 Orientamenti fisiologici nella terapia delle emopatie - Fisiological guidelines in the therapy of hemopathy

(English translation in brackets)

I centri nervosi prendono parte decisiva alla regolazione della composizione chimica e cito-morfologica del sangue (The nervous centers play a key role in the regulation of the chemical and cyto-morphologic composition of the blood).

Infatti (In fact):

  1. La stimolazione delle abenule si associa nei ratti ad aumento costante, significativo, ma transitorio del tasso delle piastrine circolanti (The habenula stimulation is associated in mice to a constant and significant but transitory, increase, of the amount of circulating platelets);
  2. Perché si avveri questa variazione numerosi fattori debbono contemporaneamente e successivamente realizzarsi (To make this happen, a number of factors must simultaneously happen too);
  3. Le variazioni del tasso piastrinemico sono versimilmente conseguenti dalla mobilitazione di Melatonina. Le variazioni stesse sono transitorie, per diversi meccanismi, general-mente a feed-back, pertinenti alla regolazione automatica del tasso piastrinemico (Variation of the platelets rate is likely to be connected to changes in mobilization of Melatonin. These changes are transitory, due to different mechanisms, usually connected to feed back responses linked to the automatic regulation of the platelet rate);
  4. Un'azione diretta la melatonina sembra esercitare sui megacariociti del midollo, che tendono a crescere in un primo tempo, dopo trattamento sistematico per via parenterale dei ratti (Melatonin seems to have a direct action on marrow’s megakaryocytes, that after parenteral injection in rats tend initially to grow);
  5. Altri organi che sembrano giocare un ruolo determinante nella regolazione del tasso piastrinemico sono i polmoni. La vagotomia uni- o bilaterale, l'atropinizzazione o la ganglioplegizzazione degli animali, il pneumotorace uni- o bilaterale, sembrano modificare decisamente la funzione di regolazione che sul tasso piastrinemico esercita l'apparato respiratorio (Another organ that seems to play a key role in the regulation of the platelet rate is the lung. The unilateral or bilateral vagotomy, the atropinisation  or the ganglioplegization of the animals, the uni or bilateral pneumothorax, seems to modify the function of regularization of the platelet rate on the respiratory system);
  6. Anche la milza e i rimanenti organi splancnici esplicano, con meccanismi in parte diversi, funzioni di regolazione non solo sul tasso piastrinemico, ma anche su quello dei linfo-monociti e dei granulociti circolanti (The spleen and the other splanchnic organs, have, with different mechanisms, the function of regulation of the platelet rate, but also of the number of lymphocytes, monocytes and of the circulating granulocytes);
  7. Le piastrine sembrano interferire sul tensioattivo alveolare, del quale riducono l'efficienza. Quest'azione può venire in parte compensata dall'ipofase del lining alveolare e dalle plasmaproteine (The platelets seem to interfere on the efficiency of the alveolar surfactant. This action can be partially being compensated from the ipophase of the alveolar lining and from the plasmaproteins);
  8. Sembrano esercitare una funzione significativa sul tensioattivo anche i linfo-monociti in particolari condizioni (In particular conditions seems to have a significant action on the alveolar surfactant and limpho monocytes);
  9. Queste influenze sulla funzione del polmone vengono svelate sia dalle curve P/V di inflazione e di deflazione dei polmoni, come dalla determinazione dello «Stability Ratio», col metodo di Pattle (These modifications of the lung functions, are confirmed by the P/V curve of inflation and deflation of the lungs, as in the determination of the "Stability Ratio" with the Pattle's Method);
  10. Nell'uomo la melatonina stimola alla proliferazione gli elementi della serie mieloide, eritroide e magacariocitica del midollo (In humans, the melatonin stimulated the proliferation of the elements of the myeloid, erythroid and megakaryocytic series of the marrow);
  11. Eccellenti risultati di valore terapeutico definitivo si sono ottenuti con la melatonina non solo in diverse forme di trombocitopenie, accompagnate o meno da porpore, bensì anche in alcuni stati trombocitopenici delle leucosi linfoidi (Excellent results, with defined therapeutic value were obtained with melatonin, not only in several types of thrombocytopenia, with or without the appearance of purpurae, but also in some thrombocytopenic cases of lymphoid leucosis);
  12. La melatonina manifesta significativi effetti per os, già a dosi di pochi µg, ripetuti o meno nelle 24 ore. Anche somministrata per via intramuscolare o endovena la melatonina è ugualmente ben tollerata. A piccole dosi per os, il colorito della cute diventa più marcatamente roseo, per probabile maggior trasparenza dell'epidermide, mentre si modificano le caratteristiche comportamentali con accentuazione della motilità spontanea, diminuzione del senso di stanchezza, accentuazione della percezione subbiettiva di benessere. L'iniezione e.v. troppo rapida provoca sonnolenza ed un senso di stordimento (The melatonin shows significant effects per os, in doses of few μg even if not repeated during the day. Intramuscular or intravenous injection is well tolerated. With small doses per os, the color of the skin becomes markedly rosy, probably due to a major transparency of  the epidermis, but behavioral features result modified with an increase of the spontaneous motility, diminished fatigue and emphasis of the perception of wellness. A fast intravenous injection leads to drowsiness and daze);
  13. Nelle mielosi arigenerative di soggetti attempati il tasso piastrinemico stenta a risalire sotto l'effetto della melatonina. Tuttavia pur con tassi di 25-30.000, od anche più bassi, di piastrine, le petecchie e le suffusioni emorragiche cutanee e mucose si presentano molto più raramente. Le piastrine d'altra parte tendono ad assumere forma discoidale, ed a crescere di diametro. Per queste ragioni, e per altre ancora, sembra che le interazioni fra piastrine ed endotelio, relative soprattutto al trofismo di quest'ultimo, siano orientate in senso decisamente favorevole dopo somministrazione di melatonina (In arigenerative myelosis in old people, the platelets rate struggles to rise again under the effect of Melatonin. However, even with a platelet rate of 25-30.000, or lower, petechiae, cutaneous and mucosal bleeding occur very rarely. The platelets however, tend to get a discoid shape with an increased diameter. For these reasons and for many more seems that the interaction between platelets and endothelium, related to the tropism of the latter are improving after administration of melatonin);
  14. Si discutono i probabili meccanismi d'azione della melatonina (The mechanisms of action of melatonin still under discussion are):

    - Sulla piastrinopoiesi megacariocitica (About the megakaryocytic platelet-genesis);

    - Sul contenuto dei corpi densi in ATP delle piastrine circolanti (About the content of dense bodies in ATP of circulating platelets);

    - Sulle interazioni fra melatonina e trombostenina (About the interactions between Melatonin and Thrombosthenin);

    - sulle somiglianze e differenze fra l'azione della Vincristina e Vincaleucoblastina da una parte, e della Melatonina dall'altra (About the similarities and different mechanism of action of Vincristine and vincaleukoblastine from one side and melatonin on the other);

    - Sulle possibili influenze della melatonina sull'*- e sul ß- MSH (About possible influence of melatonin on *- and on ß- MSH);

    - Sulle interferenze centrali diencefaliche, e periferiche, sui melanofori e sugli elementi staminali dl sangue, e se ne traggono eventuali future deduzioni sopra l'eziopatogenesi e la terapia di altre emopatie (About the di-encephalic and peripheral interferences on melanophores and on the stem elements of the blood, and there are further deductions about the etiopathogenesis of the therapy of others hematologic diseases).

 

 

Thereafter, the use of the solution of retinoids and the other components of Di Bella Method (DBM), was announced in a report at the Kyoto World Congress of Hematology, in 1976: Physiological Basis for a rational therapy of bone marrow diseases - XVIth Internat. Cong. Of Hematol. - September 5-11 1976 - Kyoto - Japan:

 

 

Abstract

L. Di Bella, M.T. Rossi and G. Scalera (Istituto di Fisiologia Umana, Cattedra di Fisiologia Generale Istituti Biologici, Modena, Italy)

Physiological Basis for a Rational Therapy of Bone Marrow Diseases.

The reproduction, differentiation and realease of blood cells from bone marrow seem to be governed by metabolic products, by water displacement from cellular to intercellular compartment, by neuro-hormonal agents, by poietin formation and activation. Urea and uric acid increase the bone marrow density distribution, and probably accelerate maturation of granulocytes.

Bone marrow extracellular normal hyperosmolar fluid seems to play a role in mitogenesis and differentiation of bone marrow cells. Some leukemic patients suffer nocturnal diuresis due to a probable biorhythmic deficiency of dispensable adiuretin, during a leukemia relapse.

Cell water content probably reduces during maturation as a consequence of organic phosphate compounds accumulation, of intracellular pH depression, of ATP, GTP, and other nucleotides polymerization in dense bodies, under the influence of hormones and neural transmitters, like nor-adrenalin, 5-OH-tryptamin, dopamin and 5-OH-dopamin.

Melatonin (MLT), however, seems to play a dominant role, inasmuch as: a) habenular nuclei stimulation induces thrombocitosis; b) i.v., injected MLT induces blood platelet rise in thrombocytopenic patients; and c) systematic oral or parenteral administration of MLT induces a seemingly healing state from acute or chronic lumphocytic leukemia. MSH and ACTH, or shorter corresponding polypeptide chains, seem to play as much an important role for a normal bone marrow function as MLT.

The aforesaid factors validly contribute to effectuate the formation and activation of erythro-thrombo-, and leukopoietins. The relative trouble reveals through a decrease of red blood cells and platelet blood count, as well as with a rise of eosinophil cell blood count.

 


 

As well as at the International Congress on the Pineal gland, in 1978, and published on Perspectives in Pineal functions, Progress in Brain Research, vol. 52, Elsevier Publ. Co., Amsterdam, 1979 (Session III – Physiology and Endocrinology).

The only positive element of DBM pseudo-experimentation in 1998 can be considered the ministerial codification of Di Bella method, in wich retinoids solution is an essential component.

In 2004 was published the monograph The Di Bella Method, with a large chapter on biochemical and molecular anticancer mechanisms of Retinoic Acid in the DBM multi therapeutic context.

By now several clinical studies on the DBM have been published, available on the top medical and scientific official database PubMed on the use of retinoids in the DBM context on over 800 patients.

They are about documented and verifiable facts! But in these days media have exalted with great emphasis as spectacular and innovative the "discovery" by researchers of University La Sapienza, coordinated by Elio Ziparo in collaboration with the Comprehensive Cancer Center of Cleveland (Ohio), about the use (still on cells in vitro and/or animal testing! See below Fig.7, in the publication) of retinoic acid for anticancer function, published on the review Proceedings of the National Academy of Sciences (PNAS):

 

 

 

Abstract

Toll-like receptor 3 (TLR3) activation induces microRNA-dependent reexpression of functional RARβ and tumor regression.

Toll-like receptor 3 (TLR3) is a key effector of the innate immune system against viruses. Activation of TLR3 exerts an antitumoral effect through a mechanism of action still poorly understood. Here we show that TLR3 activation by polyinosinic:polycytidylic acid induces up-regulation of microRNA-29b, -29c, -148b, and -152 in tumor-derived cell lines and primary tumors. In turn, these microRNAs induce reexpression of epigenetically silenced genes by targeting DNA methyltransferases. In DU145 and TRAMP-C1 prostate and MDA-MB-231 breast cancer cells, we demonstrated that polyinosinic:polycytidylic acid-mediated activation of TLR3 induces microRNAs targeting DNA methyltransferases, leading to demethylation and reexpression of the oncosuppressor retinoic acid receptor beta (RARβ). As a result, cancer cells become sensitive to retinoic acid and undergo apoptosis both in vitro and in vivo. This study provides evidence of an antitumoral mechanism of action upon TLR3 activation and the biological rationale for a combined TLR3 agonist/retinoic acid treatment of prostate and breast cancer.

 



Download the complete article

 

About this publication.

 

 

 

Retinoid Solution

A tipical bottle of Retinoid Solution used in Di Bella's method. The drug is not available for sale like other chemical medications but has to be prepared by a pharmacist.

  • All-Trans Retinoic Acid - Axerophthol palmitate - Betacarotene - Alpha tocopheryl acetate;

These molecules are mixed in solution form, a formulation that allows maximum bioavailability, in these ratios:

- All-Trans Retinoic Acid 0.5 gr;

- Axerophthol palmitate 0.5 gr;

- Betacarotene 2 gr;

- Alpha tocopheryl acetate 1,000 gr.

Retinoid Soluti...

...whilst it has been successfully applied in humans by the DBM since more than 40 years (Figure Retinoid Solution), e.g.: Prostatic Adenocarcinoma Gleason 3+4, Outcome of neoplastic metastases of breast cancerDuctal and Infiltrating CarcinomaDuctal Infiltrating NeoplasmPlurifocal Breast CarcinomaPlurifocal Breast Carcinoma (2), Retrospective observational clinical study on 122 cases of breast cancer !

 

 

 

NOTE: Is significant the fact that one of the co-signatories of this "so innovative and original discovery", Professor Carlo Maria Croce, director of the Comprehensive Cancer Center in Cleveland, in 1999 exhibited himself with coarse insults to Prof. Luigi Di Bella declaring: "In Italy, every couple of years, some wizard jumps up saying that cure cancer. They did it for many years and the last of this long series of sorcerers is Di Bella!".

 

Thank you for your attention. Best regards.

Giuseppe Di Bella

 


 

Translated by: Giulia P. and Angelo Bella