Researchers rethink fenretinide for prevention of oral cancer

In continuation of my update on fenretinide...

For more than two decades, researchers have studied and used fenretinide, a synthetic vitamin A derivative. Fenretinide's capacity to induce both terminal differentiation and cell death yielded highly promising results with cultured human cancer cells. Likewise, studies in lung, breast skin, prostate and bladder animal cancer models re-enforced fenretinide's cancer-preventing effects at the in vivo level. However, when it came to prevention of oral cancer,  fenretinide efficacy wasn't what scientists expected. After multiple studies with lackluster results, oral cancer researchers moved away from fentretinide to look elsewhere for an answer. 

Now researchers lead by Dr. Susan Mallery started rethinking about the failure and  wanted to find  a way to circumvent issues with poor systemic uptake by delivering the compound directly to the lesion. 

Mallery found the answer in partnering with two University of Michigan pharmaceutical chemists (Steven Schwendeman and Kashappa Goud Desai) to develop a first of its kind patch that sticks to the inside of the mouth, and delivers a continuous therapeutic dose of fenretinide directly to the precancerous lesion. The patch consists of three layers: a disk saturated with fenretinide and polymers that make the lipid soluble fenretinide better adsorbed in a water-rich environment, a secondary adhesive ring to hold the disk in place, and a final backing layer that ensures the medication stays inside the area of the patch.

The research team has just completed a pharmacokinetic study in rabbits. Subsequent plans include an initial Phase zero study in humans, followed by a clinical trial to evaluate efficacy in patients with precancerous oral lesions. A companion formulation designed to prevent emergence of pre-cancerous cells within the entire mouth may also be used in the fenretinide patch clinical trial. 

Ref : http://cancer.osu.edu/mediaroom/releases/Pages/Oral-Patch.aspx

Synthetic derivative of Retinoic acid can induce cell death

Retinoic acid (RA), a natural derivative of vitamin A, is the basis of a number of treatments against cancer. Nevertheless, it has certain disadvantages, such as the possibility of the appearance of retinoic acid syndrome, present in 25 % of cases and which can lead to death. The development of 4-HPR (see structure -Fenretinide 4-hydroxy(phenyl)retinamide) a synthetic derivative of RA, has meant a considerable advance due to its greater efficacy compared to its predecessor. It is able to induce the death of tumour cells as the method for reducing their proliferation, in a precise manner and without serious damage to surrounding tissue. Moreover, it halts the referred-to retinoic acid syndrome and even functions with cells that resist RA. In vitro studies corroborate its effectiveness as a chemopreventive agent and also as a chemotherapeutic agent, both with leukaemias and with ovary, breast or brain tumour cells.

Biologist Ms Aintzane Apraiz studied the 4-HPR in depth, focusing on the causes that, according to previous research, give rise to this ability to induce cell death. To this end, she applied this synthetic derivative to acute lymphoblastic leukaemia T cells (LLA-T). Her PhD thesis, defended at the University of the Basque Country (UPV/EHU), is entitled Role of sphingolipids and oxidative stress in the antineoplasic activity of 4-HPR: study in a leucemia model.

Amongst the various processes that can induce cell death, in the case of 4-HPR, apoptosis is outstanding; a precise mechanism and without inflammatory processes or serious damage to surrounding tissue. According to Ms Apraiz, previous research on LLA-T undertaken by the team of which she is a member, showed that 4-HPR induced a massive accumulation of ceramides (lipids of the cell membrane) and of reactive oxygen species (ROS), both of which can cause cell death. 

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