AVEMAR

Pancreas 2001 Aug; 23(2): 141-147
Wheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells
Boros LG, Lapis K, Szende B, Tomoskozi-Farkas R, Balogh A, Boren J, Marin S, Cascante M, Hidvegi M
UCLA School of Medicine, Harbor-UCLA Research and Education Institute, Torrance, California 90502, USA

The fermented wheat germ extract with standardized benzoquinone composition has potent tumor propagation inhibitory properties. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the single tracer with biologic gas chromatography-mass spectrometry. MIA cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent decrease in cell glucose consumption. uptake of isotope into ribosomal RNA (2.4%, 9.4%, and 28.0%), and release of 13CO2. Conversely, direct glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of cell palmitate and the 13C enrichment of acetyl units were also significantly increased with all doses of wheat germ extract. The fermented wheat germ extract controls tumor propagation primarily by regulating glucose carbon redistribution between cell proliferation-related and cell differentiation-related macromolecules. Wheat germ extract treatment is likely associated with the phosphorylation and transcriptional regulation of metabolic enzymes that are involved in glucose carbon redistribution between cell proliferation-related structural and functional macromolecules (RNA, DNA) and the direct oxidative degradation of glucose, which have devastating consequences for the proliferation and survival of pancreatic adenocarcinoma cells in culture.

Immunopharmacology 1999 Apr;41(3):183-186
Effect of MSC on the immune response of mice
Hidvegi M, Raso E, Tomoskozi-Farkas R, Szende B, Paku S, Pronai L, Bocsi J, Lapis K
Birochem, Budapest, Hungary. birochem@mail.datanet.hu

The supposed immunostimulatory actions of MSC, a new fermented wheat germ extract standardized to its benzoquinone composition (trade name: AVEMAR) were studied examining blastic transformation of peripheral blood lymphocytes of mice treated with MSC. It was found that MSC significantly increased the degree of blastic transformation caused by Concanavalin A. Using the B10LP to C57Bl skin graft system, MSC (0.03 and 3.0 g kg(-1) applied orally) acted in favour of restoring the immune function. On the other hand, 2,6-dimethoxy-p-benzoquinone (DMBQ), applied in equivalent doses (0.012 and 1.2 mg kg(-l)), did not shorten the rejection time of skin grafts. The immune restoring effect, as well as the blastic transformation enhancing potential of MSC may be exploited in various cases of decreased immune response.

Cancer Biother Radiopharm 1999 Aug; 14(4):277-289
MSC, a new benzoquinone-containing natural product with antimetastatic effect
Boros LG, Lapis K, Szende B, Tomoskozi-Farkas R, Balogh A, Boren J, Marin S, Cascante M, Hidvegi M
1st Institute of Pathology and Experimental Cancer Research, Semmelweis Medical University, Budapest, Hungary

An orally applicable fermentation product of wheat germ containing 0.04% substituted benzoquinone (MSC) has been invented by Hungarian chemists under the trade name of AVEMAR. Oral administration (3 g/kg body weight) of MSC enhances blastic transformation of splenic lymphocytes in mice. The same treatment shortens the survival time of skin grafts in a co-isogenic mouse skin transplantation model, pointing to the immune-reconstructive effect of MSC. A highly significant antimetastatic effect of MSC has been observed in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic effect of MSC--besides the immune-reconstitution--may also be due to its cell adhesion inhibitory, cell proliferation inhibitory, apoptosis enhancing, and antioxidant characteristics, also observed in our in vitro experiments. It is even more noteworthy that combined treatment with MSC and one of the following antineoplastic agents (5-FU and DTIC)--both in wide use in every day clinical practice--exhibited a significantly enhanced antimetastatic effect in appropriate metastasis models (established from C38 mouse colon carcinoma and B16 mouse melanoma respectively) as compared to the effect elicited by any component of these therapeutic compositions (MSC + 5-FU and MSC + DTIC) administered alone. The results show that the fermented wheat germ extract (MSC) has more than an additive effect and synergistically enhanced the metastasis inhibitory effect of both antineoplastic agents studied till now. It is also worthy of mention that the synchronous treatment with MSC profoundly decreased the toxic side effects of the applied antineoplastic agents (decreased weight loss etc). Based on the biological effects of MSC--shown to be non-toxic by subacute toxicology studies--this product may be used as an adjuvant in the therapy of malignant neoplasia and other diseases caused by or following immune-deficiency.

Anticancer Res 1998 Jul-Aug;18(4A):2353-8
Effect of AVEMAR and AVEMAR + vitamin C on tumor growth and metastasis in experimental animals
Hidvegi M, Raso E, Tomoskozi-Farkas R, Paku S, Lapis K, Szende B
Birochem Ltd., Budapest, Hungary

Because of the observed immunostimulatory actions of a new fermented wheat germ extract--with standardized benzoquinone composition--we have investigated the eventual tumor growth- and metastasis-inhibiting effects of this preparation (AVEMAR) applied alone or in combination with vitamin C. Tumor models of different origin [a highly metastatic variant of the Lewis lung carcinoma (3LL-HH), B16 melanoma, a rat nephroblastoma (RWT-M) and a human colon carcinoma xenograft (HCR25)]--kept in artificially immunosuppressed mice were applied. The metastasis-inhibiting effects of the treatments have been studied both in the presence and in the absence (following surgical removal) of the transplanted primary tumors. Combined treatments with AVEMAR and vitamin C--administered synchronously--profoundly inhibited the metastasis formation in all the applied tumor models while, treatments with vitamin C alone did not exert such an inhibiting effect on the metastasizing process. The degree of the observed metastasis inhibition in certain models was significant, while in others--although it was meaningful--did not prove to be significant. It is noteworthy that treatment with AVEMAR alone in certain models exerted a more pronounced inhibiting effect on metastasis formation than the synchronous combined treatment with AVEMAR and vitamin C. Furthermore, if the time schedule of the combined treatment was changed (vitamin C--instead of being administered synchronously--was given one hour after the treatments with Avemar), the vitamin C rather decreased the metastasis inhibiting effect of AVEMAR. It should be mentioned however, that in the case of rat nephroblastoma, a different response was observed: while, in the case of synchronous combination significant inhibition of metastasis formation was observed, treatment with AVEMAR alone did not produce metastasis-inhibition. It is noteworthy that in this model the metastasis-inhibiting effect of the synchronous combination treatment proved to be even more pronounced if AVEMAR was administered in a 100 times smaller dose than its regularly applied dosage. Treatment with AVEMAR and vitamin C--administered in combination or separately--in the majority of experimental models (with the exception of rat nephroblastoma) did not inhibit the growth of the primary tumors. It is reasonable, therefore, to suppose that in the observed metastasis-inhibiting effect the eventual proliferation inhibiting effect of these remedies does not play an important role. According to the results of other experiments--carried out in our laboratory in parallel with those described here--AVEMAR proved to have a meaningful immunostimulatory effect. It might therefore be suggested that the observed metastasis-inhibiting effect of this preparation may be mainly due to its immunostimulatory properties. The possible therapeutic benefits of AVEMAR and AVEMAR plus vitamin C are also discussed.

Orv Hetil. 1998 Nov 29;139 (48):2893-7. (In Hungarian)
A new benzoquinone-containing antimetastatic product
Szende B, Raso E, Hidvegi M, Tomoskozine FR, Paku S, Pronai L, Bocsi J, Lapis K. I.
Patologiai es Kiserleti Rakkutato Intezet, Semmelweis Orvostudomanyi Egyetem, Budapest

An orally applicable fermentation product of wheat germ containing 0.04% substituted benzoquinone (MSC) was invented by Hungarian chemists under the trade--name of AVEMAR. The following biological effects of this product were observed. Oral administration (3 g/kg body weight) of MSC enhances blastic transformation of splenic lymphocytes of mice. The same treatment shortens the survival time of skin grafts in co-isogenic mouse skin transplantation model, which points to immune-reconstructive effect of MSC. Highly significant anti-metastatic effect of MSC was observed in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic activity of MSC--besides the immune reconstitution--may also due to the cell-adhesion inhibitory, cell proliferation inhibitory, apoptosis-enhancing and antioxidant effects, which were also observed in our in vitro experiments. Based on the biological effects of MSC--which is non-toxic, according to subacute toxicology studies--this product may be used as an adjuvant in the therapy of malignant neoplasia and other diseases caused by or following immunedeprivation.

8th European Congress on Biotechnology. Budapest, Hungary, 17-21 August 1997
OPTIMIZATION OF CEREAL GERM FERMENTATION
Rita Tomoskozi-Farkas, Mate Hidvegi

One of the most important problems of cancer therapy is preventing metastasis. In the last few years researchers have been devoting more attention to immunostimulants and drugs of natural origin. Albert Szent-Gyorgyi worked on compound - 2,6-dimethoxy-p-benzoquinone (2,6-DMBQ) and 2-methoxy-benzoquinone (2MBQ) - which have anticancer and bacteriostatic effect as well. The aim of our work is to produce a drug of natural origin rich in 2-MBQ and 2,6-DMBQ which may suitable for in vivo experiments. By the reason of our previous studies we tried to increase the concentration of 2-MBQ and 2,6-DMBQ in wheat germ by yeast fermentation. To reach the optimal parameters of fermentation we used factorial design method. The simultaneous effect of reaction parameters and component concentrations on the 2,6-DMBQ formation was investigated.For the determination of the optimal 2,6-DMBQ formation the fermentation time was varied between 5 and 24 hours. The temperature range used was 25- 35 oC. The substrate - yeast ratio, the dried material - water ratio were varied between 1.5-3.5 and 5-10. We examined the effect of defatting of wheat germ, the intensity of mixing and light.

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