Clinical study of recombinant adenovirus-p53 combined with fractionated stereotactic radiotherapy for hepatocellular carcinoma.

Cancer Center, Daping Hospital and Institute of Surgery Research, Third Military Medical University, 400042, Chongqing, China.
Journal of Cancer Research and Clinical Oncology (Impact Factor: 3.01). 10/2009; 136(4):625-30. DOI: 10.1007/s00432-009-0701-6
Source: PubMed

ABSTRACT The purpose of our study was to evaluate the feasibility and treatment outcomes of recombinant adenovirus-p53 (rAd-p53, trademarked as Gendicine) combined with fractionated stereotactic radiotherapy (fSRT) in treatment of primary hepatocellular carcinoma (HCC).
We randomly enrolled 40 patients with HCC treated by fSRT alone (fSRT group) or rAd-p53 combined with fSRT (combined group). Tumor size was 2-5.2 cm (average 3.2 cm). We prescribed 50 Gy in 10 fractions at the 50%-80% isodose line of the planning target volume for 2 weeks in two groups. The combined group was treated with two intratumoral injections of rAd-p53 on day 1 and 8 while fSRT started on day 3. Tumor response was assessed after treatment using modified WHO criteria. The follow-up period was 11-44 months (median 35 months).
The overall response rate of fSRT group was 70%, with 4 patients showing complete response (20%), 10 partial response (50%) and 6 stable disease (30%). Correspondingly the overall response rate of combined group was 85%, with 7 patients showing complete response (35%), 10 partial response (50%) and 3 stable disease (15%). The 1-year survival rates of fSRT group and combined group were 70.0% and 90.0%, respectively. The 1-year disease-free survival rates of fSRT group and combined group were 65% and 85%, respectively. These treatments were well tolerated, because grade 3 or 4 toxicity was not observed.
These results suggest that rAd-p53 combined with fSRT is a relatively safe and effective method for treating primary hepatocellular carcinoma compared with only fSRT. Thus, rAd-p53 combined with fractionated SRT may be preferred as a choice of local treatment for primary HCC when the patients are inoperable or when the patients refuse operation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Wild-type p53 gene is an essential cancer suppressor gene which plays an important role in carcinogenesis and malignant progressions. The p53 gene family participates in almost all the key procedures of cancer biology, such as programmed cell death, angiogenesis, metabolism and epithelial-mesenchymal transition. The mutation or functional defects of the p53 gene family are detected in most of the solid malignant tumors, and the restoration of the p53 gene by adenovirus-mediated gene therapy becomes a promising treatment for cancer patients now.Areas covered: In the present review, the potential therapeutic effects of recombinant adenovirus p53 rAd-p53 (Gendicine™) were reviewed to explore the biological mechanism underlying the adenovirus-mediated p53 gene therapy. Then, the key points of the drug administration were discussed, including the routes of administration, dosage calculation and treatment cycles, based on findings of the preclinical and clinical trials in order to establish a standard treatment for the p53 gene therapy.Expert opinion: As an important part of the combined therapy for the cancer patients, the adenovirus-mediated p53 gene therapy was blossomed to be a promising treatment strategy. A new evaluation criteria and guideline for the gene therapy is urgently needed for the further clinical practice.
    Expert Opinion on Biological Therapy 12/2014; 15(3). DOI:10.1517/14712598.2015.990882 · 3.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gene therapy has promised to be a highly effective antitumor treatment by introducing a tumor suppressor gene or the abrogation of an oncogene. Among the potential therapeutic transgenes, the tumor suppressor gene p53 serves as an attractive target. Restoration of wild-type p53 function in tumors can be achieved by introduction of an intact complementary deoxyribonucleic acid copy of the p53 gene using a suitable viral vector, in most cases an adenoviral vector (Adp53). Preclinical in vitro and in vivo studies have shown that Adp53 triggers a dramatic tumor regression response in various cancers. These viruses are engineered to lack certain early proteins and are thus replication defective, including Gendicine, SCH-58500, and Advexin. Several types of tumor-specific p53-expressing conditionally replicating adenovirus vectors (known as replication-competent CRAdp53 vectors) have been developed, such as ONYX 015, AdDelta24-p53, SG600-p53, OBP-702, and H101. Various clinical trials have been conducted to investigate the safety and efficiency of these adenoviral vectors. In this review we will talk about the biological mechanisms, clinical utility, and therapeutic potentials of the replication-deficient Adp53-based and replication-competent CRAdp53-based gene therapy.
    OncoTargets and Therapy 01/2014; 7:1901-9. DOI:10.2147/OTT.S50483 · 1.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: P53 is the most frequently mutated gene in human cancer, but until recently was believed to be “undruggable”.•P53 is particularly frequently mutated (> 80%) in difficult to treat tumors (TNBC, HGS ovarian, squamous lung cancer).•Several drugs are now available that can reactivate mutant p53 to a form exhibiting wild-type properties (eg, PRIMA1MET).•Other compounds are available that block the degradation of wild-type p53 (e.g., nutlins).•p53-targeting drugs currently undergoing clinical trials include PRIMA1MET (APR-246) and nutlin derivatives.
    Cancer Treatment Reviews 10/2014; 40(10). DOI:10.1016/j.ctrv.2014.10.004 · 6.47 Impact Factor