Induced and repressed genes after irradiation sensitizing by pentoxyphylline.
Aim in cancer therapy is to increase the therapeutic ratio eliminating the disease while minimizing toxicity to normal tissues. Radiation therapy is a main component in targeting cancer. Radiosensitizing agents like pentoxyphylline (PTX) have been evaluated to improve radiotherapy. Commonly, cells respond to radiation by the activation of specific early and late response genes as well as by inhibition of genes, which are expressed under normal conditions. A display of the genetic distinctions at the level of transcription is given here to characterize the molecular events underlying the radiosensitizing mechanisms. The method of suppression subtractive hybridization allows the visualization of both induced and repressed genes in irradiated cells compared with cells sensitized immediately after irradiation. The genes were isolated by cDNA-cloning, differential analysis and sequence similarity search. Genes involved in protein synthesis, metabolism, proteolysis and transcriptional regulation were detected. It is important that genes like KIAA280, which were only known as unidentified EST sequences before without function, but inaccessible by array technology were recovered as functional genes. Database searches for PTX-induced genes detected a human mRNA completely unknown. In case of suppressed genes, we detected several mRNAs; one thereof shows homology to a hypothetical protein possibly involved in signal transduction. A further mRNA encodes the protein BM036 supposed to associate with the E2F transcription factor. A hypothetical protein H41 was detected, which may repress the Her-2/neu receptor influencing breast cancer, gliomas and prostate tumors. Radiation combined with PTX may lead to a better prognosis by down regulation of the Her-2/neu, which will be proven by clinical studies in the near future.
Waldeck
Waldemar
W
Division of Biophysics of Macromolecules, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Strunz
Anke M
AM
Müller
Gabriele
G
Hotz-Wagenblatt
Agnes
A
Wijenne
Jürgen
J
Langowski
Jörg
J
Didinger
Bernd
B
Debus
Jürgen
J
Braun
Klaus
K
D045744:Cell Line, Tumor; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects*; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D020411:Oligonucleotide Array Sequence Analysis; D010431:Pentoxifylline / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015854:Up-Regulation
D011838:Radiation-Sensitizing Agents; D010431:Pentoxifylline