cell lines have shown that ACN53 treatment produces a dose-dependent suppression of 
DNA synthesis, as measured by ^H-thymidine incorporation(9). ACN53-mediated 
suppression of tumor cell growth has been observed with a variety of p53-altered tumor 
cell lines, including those of colorectal, hepatocellular, non-small cell lung, breast, and 
ovarian origin. Tumor cell lines which are not p53-altered, as well as non-malignant cells in 
culture, exhibit little growth suppression from ACN53. In vivo studies have similarly 
shown tumor suppressive effects associated with ACN53-mediated gene therapy(9). The 
tumorigenicity in nude mice of human osteosarcoma (Saos-2) and human hepatocellular 
carcinoma (Hep3B) cells is suppressed if they are treated with rAd/p53 ex vivo prior to 
implantation. Established tumor xenografts derived from human small cell and non-small 
cell lung cancer cell lines have been treated with rAd/p53 given by local (peri tumoral 
subcutaneous) administradon, resulting in suppression of tumor growth. In addidon, a 
study of rAd/p53 given locally to established tumor xenografts composed of H69 small cell 
lung cancer cells has demonstrated increased survival in treated animals. 
1.6 S tudy Rauonale 
The use of ACN53 to treat malignant tumors of the Ever constitutes a novel form of cancer 
treatment, in which introduction of the wild-type p53 tumor suppressor gene into p53- 
altered tumors may inhibit tumor growth and thus.have beneficial clinical impact. The 
rationale for the administration of ACN53 via hepatic artery infusion is its potential to 
maximize ACN53 exposure to liver tumors while minimizing exposure to normal tissues 
outside the liver. 
1.7 Study Design 
This study seeks to determine the safety, biological efficacy, and effect of dose of ACN53 
in the local-regional gene therapy of primary and metastatic malignant tumors of the liver 
which suffer p53 alteration. The study design consists of an open-label, non-randomized, 
single-dose, dose-escalation Phase I trial. 
ACN53 will be administered by hepatic artery infusion to patients with primary 
(hepatocellular cancer) or metastatic (colorectal cancer) tumors of the liver. Study patients 
will be required to have evidence of p53 alteration in tumor tissue. The study will include 
sampling of normal and malignant tissues from the livers of patients following ACN53 
treatment. This will greatly facilitate assessments of clinical safety and biological efficacy, 
including efficiency and stability of gene transfer. Furthermore, sampling of treated tissues 
will require minimal additional morbidity for study patients. For many patients with liver 
tumors, especially patients with metastases of colorectal cancer, surgical implantation of a 
hepatic artery infusion pump and subsequent regional cytotoxic chemotherapy via hepatic 
artery infusion is an appropriate and commonly utilized therapy, as described above. When 
these patients elect to be evaluated for this therapy, the evaluation consists of hepatic artery 
catheterization and angiography, followed by exploratory laparotomy with pump 
placement. These patients will be eligible to enroll in the ACN53 study prior to pump 
placement, and will receive ACN53 by hepatic artery infusion immediately following 
angiography. The subsequent exploratory laparotomy will proceed after a period of at least 
7 days of post-treatment monitoring, and only if post-treatment monitoring discloses no 
serious adverse events and the patient is considered surgically fit. If performed, laparotomy 
will permit direct visualization of the treated area as well as provide surgically-obtained 
tumor and normal tissue for molecular and cellular analysis. Patients in whom exploratory 
laparotomy for potential pump placement is not indicated or not elected, including patients 
with hepatocellular cancer, will also be eligible to enroll in the ACN53 study, and will 
receive hepatic artery catheterization and angiography as part of the study. These patients 
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Recombinant DNA Research, Volume 20 
