Radiosensitization dependent on p53 function in bronchial carcinoma cells by the isoflavone genistein and estradiol in vitro.
OBJECTIVE
Simultaneous radiotherapy with chemotherapy is a standard treatment for inoperable non-small cell lung cancer (NSCLC), but the clinical outcome still remains poor. To further intensify treatment, substances need to be identified, which increase the effect of radiation on tumor cells without further enhancing toxicity to normal tissue. Hormones have a different toxicity profile than radiation or cytostatic drugs. As NSCLC often express estrogen receptors (ERs), the combination of genistein or estradiol and radiation in vitro was investigated.


METHODS
A549 NSCLC cells with an inducible expression of a mutated TP53 and fibroblasts of a male donor (DF-18) were examined. ER expression was immunocytologically confirmed in all studied cell lines. Clonogenic survival was measured after incubation of the cells with genistein or estradiol (0.01 microM and 10 microM as maximum clinically applicable dose) and irradiation with different doses (0-4 Gy). The differentiation state of fibroblasts after combined therapy was analyzed.


RESULTS
A549 cells expressing mutated TP53 were more radioresistant than TP53 wild-type cells. Incubation of nonfunctional TP53 cells with genistein or estradiol increased radiosensitivity in both tested concentrations. By contrast, radiosensitivity of A549 with wild-type TP53 and DF-18 was not altered by hormonal incubation. In DF-18 radiation induced growth arrest that was not increased by additional hormonal incubation.


CONCLUSIONS
NSCLC cells with nonfunctional TP53 might be sensitized against radiation by genistein or estradiol. As genistein is better tolerable than estradiol in patients, additional studies are warranted to assess potential gains of this combination therapy.
Hermann
Robert Michael
RM
Department of Radiotherapy and Radiooncology, Georg August University, Göttingen, Germany. ro.hermann@t-online.de
Fest
Jan
J
Christiansen
Hans
H
Hille
Andrea
A
Rave-Fränk
Margret
M
Nitsche
Mirko
M
Gründker
Carsten
C
Viereck
Volker
V
Jarry
Hubertus
H
Schmidberger
Heinz
H
D000328:Adult; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000502:physiology; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D019833:Genistein