Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors

Abstract

p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector containing wt p53 was carried out in patients with metastatic melanoma or breast cancer with increased p53 protein immunoreactivity in pretreatment tumor biopsies. The biological activity of the injected wt p53 was assayed by reverse transcriptase-polymerase chain reaction in tumor tissue. A total of six (five melanoma and one breast adenocarcinoma) patients were treated at dose levels dependent upon tumor size/dose escalation sequence. Five of six patients became positive for the transfer of wt p53 into tumor tissue 2 days after injection of the vector. Of the four patients assayed, all developed anti-adenoviral antibodies. Adverse reactions associated with i.t. injection were mild, with no obvious correlation between the incidence, severity, or relationship of the events and drug dose. p53 gene therapy by i.t. injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective (with respect to transduction frequency) in patients with either metastatic melanoma or breast cancer.

Adenovirus‐mediated intra‐tumoral delivery of the human endostatin gene inhibits tumor growth in nasopharyngeal carcinoma

“…40 Even if a small amount of adenoviral vectors enter into circulation, the host immune response might be limited and does not seem to significantly reduce the effectiveness of readministration. 47,48 In this study, 5 courses of intra-tumoral delivery directed high-level expression of endostatin mRNA and protein inside NPC CNE-2 xenografted tumors, in association with significant inhibition of growth and angiogenesis. These results suggest that antiangiogenic therapy may be an important future addition to the multidisciplinary therapeutic approaches for NPC.…”

“…47 When delivered intra-tumorally, adenoviruses can direct tumor-specific, therapeutically relevant transgene expression and induce local immunotherapy for tumor cells. 40 Even if a small amount of adenoviral vectors enter into circulation, the host immune response might be limited and does not seem to significantly reduce the effectiveness of readministration.…”

A comprehensive assessment of p53-responsive genes following adenoviral-p53 gene transfer in Bcl-2-expressing prostate cancer cells

“…In this regard it is noteworthy that p53 is among the principal mediators of the response to genotoxic stress and that many cancer therapeutic interventions, including ionizing radiation and chemotherapy, are predicated on the selective induction of genotoxic stress in cancer cells. Importantly, the feasibility of restoration of p53 function using adenoviral-mediated wt p53 gene transfer (Ad-p53) is currently being evaluated in clinical trials for patients with carcinoma of the lung (Swisher and Roth, 2002), prostate (Introgen, 2003), urinary bladder (Pagliaro, 2000), brain (Lang et al, 2003), breast (Dummer et al, 2000), ovary (Wen et al, 2003), and head and neck (Clayman et al, 1998(Clayman et al, , 1999. Upregulation of the antiapoptotic bcl-2 proto-oncogene is a common event in diverse malignancies including prostate cancer (MacCarthy-Morrogh et al, 1999;Moul, 1999).…”

Mutant Bik expression mediated by the enhanced minimal topoisomerase IIα promoter selectively suppressed breast tumors in an animal model

“…Multiple preclinical studies and clinical trials have demonstrated the therapeutic efficacy and minimal side effects of liposomal gene therapy for cancers. [5][6][7][8] The efficacy of gene therapy depends on the promoter activity. As breast cancer frequently develops metastasis, the new therapy should be designed for systemic administration.…”