Zweedse en Russische onderzoekers melden dat ze een middel, het molecuul PRIMA-1, hebben gevonden dat mogelijk de beschadiging van het gen P53 op DNA-niveau kan repareren. Dit is zo belangrijk omdat het gen P53 in meer dan de helft verantwoordelijk is voor het ontstaan van kanker. Zie ook een beschrijving van een onderzoek met het gen P53 en eierstokkanker onder kankersoorten-eierstokkanker.

Ik heb onderstaande artikelen niet vertaald, maar dit lijkt me voldoende voor geïnteresseerde artsen en medisch specialisten.

Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound

Vladimir J.N. Bykov1, Natalia Issaeva1, Alexandre Shilov1, 2, Monica Hultcrantz1, Elena Pugacheva3, Peter Chumakov3, Jan Bergman4, Klas G. Wiman1 & Galina Selivanova1

The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of low-molecular-weight compounds in order to identify compounds that can restore wild-type function to mutant p53. We found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53. This molecule, named PRIMA-1, restored sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. PRIMA-1 rescued both DNA contact and structural p53 mutants. In vivo studies in mice revealed an antitumor effect with no apparent toxicity. This molecule may serve as a lead compound for the development of anticancer drugs targeting mutant p53.

1. Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden
2. Institute of Cytology and Genetics, RAN, Novosibirsk, Russia
3. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
4. Department of Biosciences at Novum, Karolinska Institutet, Novum, Huddinge, Sweden
Correspondence should be addressed to K G Wiman. e-mail: klas.wiman@mtc.ki.se

More than 50% of human tumours carry mutations in TP53, so strategies to restore the activity of this tumour suppressor in cancer cells are being actively investigated by drug companies. A team of researchers in Sweden and Russia now report the discovery of a compound that reactivates p53 function and induces apoptosis in human cancer cells.

In the March issue of Nature Medicine, Bykov et al. describe a chemical library screen for compounds that selectively inhibit the growth of mutant TP53-expressing tumour cells. This led to the discovery of a small molecule that they called PRIMA-1 (p53 reactivation and induction of massive apoptosis), which inhibits the growth of cells expressing a number of different TP53 mutations. p53 is a transcription factor that suppresses tumour growth by several mechanisms, including induction of apoptosis. Bykov et al. show that treatment of tumour cells with PRIMA-1 caused a substantial increase in the number of cells undergoing caspase-mediated apoptosis. Furthermore, growth of tumours that carry p53 mutations was suppressed in mouse xenografts following both intratumoral and intravenous administration of PRIMA-1.

PRIMA-1 induced apoptosis and slowed tumour growth in a mutant p53-dependent manner. TP53 mutants that are present in a number of different human cancers fail to bind the consensus DNA binding site, and Bykov et al. showed that treatment of cells with the compound restored DNA binding to 13 out of 14 TP53 mutants. PRIMA-1 also stimulated transcription of two classic p53 target genes — p21 and MDM2 — only in cells that express mutant forms of TP53.

Bykov et al. are not sure about the exact molecular mechanism of PRIMA-1. Studies with conformation-specific monoclonal antibodies revealed that the drug restores the wild-type structure to mutant p53. PRIMA-1 also rescued this conformation in the absence of other cellular proteins, indicating its ability to directly interact with p53. The authors are planning nuclear magnetic resonance and X-ray crystallography studies to further address questions about how the compound works. Other peptides and small molecules have been previously reported to protect p53 against denaturation or restore DNA binding activity to a mutant p53 domain. PRIMA-1 is the first molecule shown to convert p53 back into a properly folded, biologically active form.

Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound
Bykov, V. J. et al.
Nature Med. 8, 282-288 (2002)
Meer informatie over het instituut dat dit onderzoek deed kunt u lezen op deze website Biomed

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