The p53 gene plays a key role in the prevention of cancer, by blocking cell growth and triggering programmed cell death or apoptosis. If, however, p53 has mutated and become defective, the cancer cells can acquire the ability to evade apoptosis and become more resistant to therapy. Researchers at Karolinska Institutet and Karolinska University Hospital in Sweden have now obtained results from the first tests using a new substance that can restore the function of defective p53 and activate apoptosis in cancer cells.
The substance is known as APR-246 and has now been tested on humans in a phase I/II study, which was conducted on 22 patients with advanced blood or prostate cancer. Some of the patients came from the Haematology Centre at the Karolinska University Hospital in, Stockholm, where the study's lead investigator, consultant Dr Sren Lehmann is based. The remainder of the patients were from other clinics in Gothenburg, Lund, Uppsala and rebro.
The patients received daily infusions of APR-246 for four days. When the researchers analyzed the cancer cells taken before and after treatment, they saw indications that the p53 gene had been activated to varying degrees, and that this had triggered the suicide program in the cancer cells. Ten patients could be evaluated as regards the development of their cancer, and in two of them there were signs of tumour regression.
However, the study was actually not designed to test the clinical effects but to ascertain how well the substance was tolerated by the body. With the main adverse reactions confined to temporary tiredness, nausea, headache and confusion, their results would suggest that the substance is well tolerated.
"The side-effects were totally different to those produced by conventional chemotherapy, which bodes well for designing combination therapies," says Dr Lehmann. "And it's in precisely this kind of combination that we think the substance has the greatest potential. I
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