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24 Mar 2016

RETINOL AND CANCER CELLS CONT

QUESTION: Vitamin E and D get a lot of press and use in oncology therapy, but you don’t hear a lot about vitamin A. Do you think it has a role in cancer? If so, at what dosage?

ANSWER: I ran across this regarding retinol and was thinking back a couple decades ago when we used it a lot in oncology. I add Retinyl palmitate or other fat sol (NO carotenoids), oral only 25,000 – 50,000 IU a day during tx in conjunction with the Poly DCA protocol, and this piece below makes me wonder about secondary prevention in BrCA (with or without Tamox).

Based on the older Neuroblastoma data avg adult dose appears to be:
50-100 mg/meter squared
Avg adult = 1.77 meter squared
177 mg
88,500 – 177,000 mcg
mcg/0.3 = IU

295,000 – 590,000 IU.

Interestingly, we have a 5 year old with AML-MLL on an adult equivalent of 150,000 IU per day (25,000 IU at 25 pounds) with the Poly DCA. I presented that trial to the OncANP. As for potential in BrCa secondary prevention I’m not sure we know.

In addition, the researchers showed that only one concentration of retinoic acid (about one micro Molar) produced the anti-cancer effects. Lower concentrations gave no change, and higher concentrations produced a smaller effect.

Can vitamin A turn back the clock on breast cancer? Pre-cancerous cells treated with a vitamin A derivative revert into non-cancerous cells – A derivative of vitamin A, known as retinoic acid, found abundantly in sweet potato and carrots, helps turn pre-cancer cells back to normal healthy breast cells, according to research published this month in the International Journal of Oncology. The research could help explain why some clinical studies have been unable to see a benefit of vitamin A on cancer: the vitamin doesn’t appear to change the course of full-blown cancer, only pre-cancerous cells, and only works at a very narrow dose. Because cells undergo many changes before they become fully aggressive and metastatic, Sandra V. Fernandez, Ph.D., Assistant Research Professor of Medical Oncology at Thomas Jefferson University, and colleagues, used a model of breast cancer progression composed of four types of cells each one representing a different stage of breast cancer: normal, pre-cancerous, cancerous and a fully aggressive model. When the researchers exposed the four breast cell types to different concentrations of retinoic acid –one of the chemicals that the body converts vitamin A into – they noticed a strong change in the pre-cancerous cells. Not only did the pre-cancerous cells begin to look more like normal cells in terms of
their shape, they also changed their genetic signature back to normal. Dr. Fernandez’s pre-cancerous cells had 443 genes that were either up or downregulated on their way to becoming cancerous. All of these genes returned to normal levels after treatment with retinoic acid. “It looks like retinoic acid exerts effects on cancer cells in part via the modulation of the epigenome,” says Fernandez. “We were able to see this effect of retinoic acid because we were looking at four distinct stages of breast cancer,” says Dr. Fernandez. “It will be interesting to see if these results can be applied to patients.” Interestingly, the cells that were considered fully cancerous did not respond at all to retinoic acid, suggesting that there may be a small window of opportunity for retinoic acid to be helpful in preventing cancer progression. In addition, the researchers showed that only one concentration of retinoic acid (about one micro Molar) produced the anti-cancer effects. Lower concentrations gave no change, and higher concentrations produced a smaller effect. The next step will be to try to learn whether the amount of retinoic acid required can be maintained in an animal model, and if that concentration will have the same effects as Dr. Fernandez observed in cells. If those studies show the same effect, the next step would be to test whether these observations hold true in humans. ”

Arisi MF, Starker RA, Addya S, Huang Y, Fernandez SV. All trans-retinoic acid (ATRA) induces re-differentiation of early transformed breast epithelial cells. Int J Oncol. 2014 Jun;44(6):1831-42. doi: 10.3892/ijo.2014.2354. Epub 2014 Mar 21. PMID: 24676586

Abstract: Retinoids have been used as potential chemotherapeutic or chemopreventive agents because of their differentiative, anti-proliferative, pro-apoptotic and antioxidant properties. We investigated the effect of all trans-retinoic acid (ATRA) at different stages of the neoplastic transformation using an in vitro
model of breast cancer progression. This model was previously developed by treating the MCF-10F human normal breast epithelial cells with high dose of estradiol and consists of four cell lines which show a progressive neoplastic transformation: MCF-10F, normal stage; trMCF, transformed MCF-10F; bsMCF, invasive stage; and caMCF, tumorigenic stage. In 3D cultures, MCF-10F cells form tubules resembling the structures in the normal mammary gland. After treatment with estradiol, these cells formed tubules and spherical masses which are indicative of transformation. Cells that only formed spherical masses in collagen were isolated (trMCF clone 11) and treated with ATRA. After treatment with 10 or 1 μM ATRA, the trMCF clone 11 cells showed tubules in collagen; 10 and 43% of the structures were tubules in cells treated with 10 and 1 μM ATRA, respectively. Gene expression studies showed that 207 genes upregulated in transformed trMCF clone 11 cells were downregulated after 1 μM ATRA treatment to levels comparable to those found in the normal breast epithelial cells MCF-10F. Furthermore, 236 genes that were downregulated in trMCF clone 11 were upregulated after 1 μM ATRA treatment to similar levels shown in normal epithelial cells. These 443 genes defined a signature of the ATRA re-programming effect. Our results showed that 1 μM ATRA was able to re-differentiate transformed cells at early stages of the neoplastic process and antagonistically regulate breast cancer associated genes. The invasive and tumorigenic cells did not show any changes in morphology after ATRA treatment. These results suggest that ATRA could be used as a chemopreventive agent to inhibit the progression of premalignant lesions of the breast.