Antagonistic interaction between bicalutamide (Casodex) and radiation in androgen-positive prostate cancer LNCaP cells.
BACKGROUND
Bicalutamide (Casodex) reportedly improves high-risk prostate cancer survival as an adjuvant treatment following radiotherapy. However, biological data for the interaction between bicalutamide and ionizing radiation in concomitant association are lacking.


METHODS
To explore this issue, androgen-dependent (LNCaP) and -independent (DU145) human prostate cancer cells were exposed for 48 hr to 20, 40, or 80 microM bicalutamide introduced before (neoadjuvant), during (concomitant), or following (adjuvant) radiation. Growth inhibition and cytotoxicity, cell cycle distribution and expression of the prostate serum antigen (PSA) and androgen receptor (AR), were measured as endpoints.


RESULTS
Bicalutamide-induced cytotoxic and cytostatic effects were found to be correlated with a marked G1 phase arrest and S phase depression. The drug down-regulated PSA and AR proteins and psa mRNA in LNCaP cells. However, transient up-regulation of the expression of ar mRNA was observed in the presence of 40 microM drug. DU145 cells did not express PSA and proved to be comparatively resistant to the drug from both cytostatic and cytotoxic effects. Bicalutamide dose-dependently induced a significant decrease of radiation susceptibility among drug survivors in LNCaP cells, whilst the interaction appeared to be additive in DU145 cells.


CONCLUSIONS
The antagonistic radiation-drug interaction observed in LNCaP cells is of significance in relation to combined radiotherapy-bicalutamide treatments directed against tumors expressing the AR. The results suggest that bicalutamide is amenable to combined schedule with radiotherapy provided the drug and radiation are not given in close temporal proximity.
Quéro
Laurent
L
Institut Curie, Bât. 110-112, Centre Universitaire, Orsay, France.
Giocanti
Nicole
N
Hennequin
Christophe
C
Favaudon
Vincent
V
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016193:G1 Phase / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018714:Radiotherapy, Adjuvant; D011944:Receptors, Androgen / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D014105:Tosyl Compounds / Q000494:pharmacology*
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D017430:Prostate-Specific Antigen