Clinical study of recombinant adenovirus-p53 combined with fractionated stereotactic radiotherapy for hepatocellular carcinoma
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.
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- "Small clinical trials with Ad-p53 have also been carried out in patients with hepatocellular cancer, ovarian cancer, esophageal cancer and gliomas (for review, see Refs.  ). Overall, the main conclusion from these trials is that Ad-p53 is relatively free of major toxicity but has limited efficacy. "
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 · 7.59 Impact Factor
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- "The E1-defective replication-incompetent adenoviral vectors used earlier are incapable of replication; the safety is guaranteed but the infection of each tumor cell is impossible, which limited its therapeutic effect. The world first anti-tumor gene therapeutic drug, recombinant human P53 adenovirus (Ad- P53), which was approved by the State Food and Drug Administration (SFDA) of China in 2004, belongs to this replicationincompetent adenoviral vector (Lu et al., 2011; Yang et al., 2010; Peng, 2005). More recently, the conditionally replicative adenovirus (CRAd), which can replicate specifically in tumor cells and can therefore infect, kill more tumor cells (also called oncolytic adenovirus) has been developed; the early representative of oncolytic adenovirus was Onyx-015 (Bagheri et al., 2011; Hemminki et al., 2011; He et al., 2009; Opyrchal et al., 2009). "
ABSTRACT: Gene therapy has become an important strategy for treatment of malignancies, but problems remains concerning the low gene transferring efficiency, poor transgene expression and limited targeting specific tumors, which have greatly hampered the clinical application of tumor gene therapy. Gallbladder cancer is characterized by rapid progress, poor prognosis, and aberrantly high expression of Survivin. In the present study, we used a human tumor-specific Survivin promoter-regulated oncolytic adenovirus vector carrying P53 gene, whose anti-cancer effect has been widely confirmed, to construct a wide spectrum, specific, safe, effective gene-viral therapy system, AdSurp-P53. Examining expression of enhanced green fluorecent protein (EGFP), E1A and the target gene P53 in the oncolytic adenovirus system validated that Survivin promoter-regulated oncolytic adenovirus had high proliferation activity and high P53 expression in Survivin-positive gallbladder cancer cells. Our in vitro cytotoxicity experiment demonstrated that AdSurp-P53 possessed a stronger cytotoxic effect against gallbladder cancer cells and hepatic cancer cells. The survival rate of EH-GB1 cells was lower than 40% after infection of AdSurp-P53 at multiplicity of infection (MOI) = 1 pfu/cell, while the rate was higher than 90% after infection of Ad-P53 at the same MOI, demonstrating that AdSurp-P53 has a potent cytotoxicity against EH-GB1 cells. The tumor growth was greatly inhibited in nude mice bearing EH-GB1 xenografts when the total dose of AdSurp-P53 was 1 × 10(9) pfu, and terminal dUTP nick end-labeling (TUNEL) revealed that the apoptotic rate of cancer cells was (33.4 ± 8.4)%. This oncolytic adenovirus system overcomes the long-standing shortcomings of gene therapy: poor transgene expression and targeting of only specific tumors, with its therapeutic effect better than the traditional Ad-P53 therapy regimen already on market; our system might be used for patients with advanced gallbladder cancer and other cancers, who are not sensitive to chemotherapy, radiotherapy, or who lost their chance for surgical treatment.Molecular oncology 12/2011; 5(6):545-54. DOI:10.1016/j.molonc.2011.10.001 · 5.33 Impact Factor
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- "Despite remarkable examples of therapeutic efficacy in patients with Li-Fraumeni syndrome, an autosomal-dominant mutation of the p53 gene, the Food and Drug Administration (FDA) did not approve Advexin, the western version of a wt-p53-encoding adenovirus developed by Introgen Therapeutics. Nevertheless , the equivalent Gendicine, in combination with radiotherapy , is being applied in the treatment of head and neck cancer in China since several years and also shows efficacy in the combination treatment of hepatocellular carcinoma (Shi and Zheng, 2009; Yang et al., 2010). "
ABSTRACT: The p53 tumour suppressor blocks cancer development by triggering apoptosis or cellular senescence in response to oncogenic stress or DNA damage. Consequently, the p53 signalling pathway is virtually always inactivated in human cancer cells. This unifying feature has commenced tremendous efforts to develop p53-based anti-cancer therapies. Different strategies exist that are adapted to the mechanisms of p53 inactivation. In p53-mutated tumours, delivery of wild-type p53 by adenovirus-based gene therapy is now practised in China. Also, remarkable progress has been made in the development of p53-binding drugs that can rescue and reactivate the function of mutant or misfolded p53. Other biologic approaches include the development of oncolytic viruses that are designed to specifically replicate in and kill p53-defective cells. Inactivation of wt-p53 frequently results from dysregulation of MDM2, an E3 ligase that regulates p53 levels. Small-molecule drugs that inhibit the interaction of MDM2 and p53 and block p53 degradation are currently tested in clinical trials. This survey highlights the recent developments that attempt to modulate the function of p53 and outlines strategies that are being investigated for pharmacological intervention in the p53 pathway.British Journal of Pharmacology 06/2011; 165(2):328-44. DOI:10.1111/j.1476-5381.2011.01570.x · 4.84 Impact Factor