Prostate cancer radiosensitization in vivo with adenovirus-mediated p53 gene therapy

Didier Cowen, Naji Salem, Faramarz Ashoori, Ray Meyn, Marvin L. Meistrich, Jack A. Roth, Alan Pollack

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

An adenovirus 5 vector containing wild-type p53 cDNA (Ad5-p53) and a cytomegalovirus promoter was used to generate p53 transgene expression. Control vector (Ad5-pA) contained the poly-adenosine sequence. PC3 cells (2 x 106) were injected s.c. into the legs of nude mice. Treatment with Ad5-p53 was initiated at a tumor volume of 200 mm3. Three intratumoral injections (days 1, 4, and 7) were given with 3 x 108 plaque-forming units, followed by 5 Gy pelvic irradiation (day 8) in one fraction using a cobalt-60 source. Tumor volume measurements were obtained every 2 days. LNCaP cells (2 x 106) were injected orthotopically into the prostates of nude mice, and tumor weight was approximated using serum prostate-specific antigen (PSA) obtained from weekly tail vein bleedings. The target PSA for the start of the studies was 5 ng/ml. The intraprostatic injections of Ad5-p53 were done twice (days 1 and 2) and followed by 5 Gy pelvic irradiation on day 3. The PC3 tumor volume growth curves were log transformed and fitted using linear regression. The times (in days) for the tumors to reach 500 mm3 were calculated as 10.7 ± 0.7 (± SE) for the saline control (no virus), 9.8 ± 2.1 for Ad5-pA, 15.6 ± 1.6 for Ad5-p53, 14.6 ± 1.5 radiation therapy (RT; 5 Gy), 14.6 ± 1.5 for Ad5-pA plus RT, and 31.4 ± 5.3 for Ad5-p53 plus RT. The Ad5-p53 plus RT times were significantly different from the other groups. An enhancement factor of 3.4 was calculated, indicating supra-additivity. LNCaP tumor growth was determined via weekly serum PSA measurements. Treatment failure was determined using two PSA-based methods; a serum PSA of >1.5 ng/ml or two rises in PSA during 6 weeks posttreatment. The results were similar using either end point. Treatment with Ad5-p53 plus 5 Gy resulted in significantly fewer PSA failures (<30%), as compared with Ad5-p53 alone (64-73%) and the other controls (~80-100%) These results are also consistent with a supra-additive inhibition of tumor growth. Tumor growth in vivo was inhibited supra-additively when p53(null) and p53(wildtype) prostate tumors were treated with Ad5-p53 and 5 Gy radiation.

Original languageEnglish (US)
Pages (from-to)4402-4408
Number of pages7
JournalClinical Cancer Research
Volume6
Issue number11
StatePublished - Jan 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Prostate cancer radiosensitization in vivo with adenovirus-mediated p53 gene therapy'. Together they form a unique fingerprint.

  • Cite this

    Cowen, D., Salem, N., Ashoori, F., Meyn, R., Meistrich, M. L., Roth, J. A., & Pollack, A. (2000). Prostate cancer radiosensitization in vivo with adenovirus-mediated p53 gene therapy. Clinical Cancer Research, 6(11), 4402-4408.