Hepatic Arterial Infusion (HAI) and gene therapy are two promising new technologies for treating colorectal cancer. HAI involves directly infusing chemotherapy agents into the hepatic artery to target cancer cells in the liver before they reach 2-3mm in size. A pump is implanted to slowly deliver drugs like floxuridine. Gene therapy aims to correct single gene defects by inserting functional genes using viral vectors, but faces challenges with delivery and preventing immune rejection. Both techniques have advantages for colorectal cancer treatment after resection, but also limitations requiring further development.

1. NEW TREATMENT TECHNOLOGY
FOR COLORECTAL CANCER
Hepatic Arterial Infusion (HAI)
 HAI rationale
Principle of HAI:
 Tumour cells derived from the gastrointestinal tract (GI)
from malignant gastrointestines, particularly CRC disperse in
hematogenic manner through portal circulation. Hence, the
initial occurrence of metastasis is the liver.
 Before the hepatic metastases reach 2-3 mm in size, it derives
its blood supply is from the hepatic artery, while healthy
hepatocyes all supplied by the portal circulation.
Consequently, hepatic metastases is difficult to reach by
infusion chemotherapy.
 Floxuridine, FUDR infused into hepatic arterial circulation
produces the least toxic effect even in high concentration.
 Technical aspects of HAI
1) Infusion technique
A pump is place in the subcutaneous tissue. This pump is able to retain
30-50 ml of fluid, dispensing FUDR at a slow fixed rate. The reservoir is
stored with a a couple of weeks worth of chemotherapy with
subsequent infusion design to hold for another couple of weeks
installed with heparin saline. The persistent delivery reduce imminent
thrombosis while promoting a user-friendly mobile approach. This
pump also permit direct delivery to catheter without disturbing the
reservoir.
2) Positioning of pump
 A catheter is placed within gastro duodenum,
while the vessels which are adjacent to the
pancreas, duodenum and stomach are legated
to eliminate organ perfusion.
Cholecystectomy is performed
prophylactically to prevent cholecystits.
Intraoperatively, fluorescein is injected onto
side ports to examine liver perfusion. Prior to
surgical intervention, review of liver perfusion Fig. 2
is implemented with the use of technetium scan; macro aggregated
albumin perfusion is use to identify any risks of arteriovenous
shunting. To assure the perfusion of extra hepatic, arteriogram is
conducted, embolizing the targeted vessel.
 Advantages of HAI- FUDR (Floxuridine)
 Tumour absorbs 99% of the drug FUDR at its first pass.
 Since drug concentration in surrounding tissues of liver is
low, side effect is low eg. nausea.
 FUDR is injected to tumour via liver arteries where the
chemotherapy agent work actively.
 Possibility of shrinking tumours is prominent with direct
FUDR administration to blood vessels of liver arteries.
 It was postulated that even with 5-FU agent treated for
increase tumour size, these tumours still decrease in size
with chemotherapy pertaining to intra-arterial in estimated
occurrence of 50%.
Introduction:
Colorectal cancers are cancerous growths found in the colon, rectum and appendix. It is formed from
cells which line the mucosa of the colon and rectum. It begins as non-invasive but if
undetected, the cancer will grow bigger and project into the lumen of the colon. Colorectal
cancer is the second commonest fatal malignancy in both sexes combined after lung cancer,
and when it has invaded the lymph nodes or the liver or other distant organs is in the
advanced stage.
Gene Transfer
 Gene transfer rationale
Gene therapy is the insertion of genes into
an individual's cells and tissues to treat a
disease, and hereditary diseases in
which a defective mutant allele is replaced
with a functional one.
Gene therapy is most applicable in the
correction of the single gene defect,
which causes the disease phenotype. Fig. 1
In colon cancer, this goal is elusive as malignant transformation is usually
accompanied by a series of genetic mutations. The p53 gene mutations are
important for the propagation of the malignant phenotype. These
mutations are corrected by the corollary and the inhibiting of the growth
of tumour cells.
The cell cycle is regulated by the p53 gene and it can cause growth arrest
or apoptosis in response to DNA damage. Loss of p53 control leads to
uncontrolled growth and is associated with more aggressive tumours. The
growth of the tumours will be inhibited when the wild-type p53 is
restored in the p53 mutated tumours.
 Technical aspects of gene transfer
 Gene transfer involves the introduction of a foreign gene into
the cancer cell or surrounding tissue.
 For this therapy, it is implemented by using:
 Suicide genes which causes cellular death when expressed.
 Antiangiogenesis genes and cellular death stasis genes.
 Different viral vector to deliver these genes, but mostly a
replication incompetent adenovirus.
 Limitations and current development:
Initial implement gene transfer therapy have highlighted it promise, as
well as some delivery difficulties. The therapeutic gene has to be delivered
to the target cells effectively and elicits a response. It is difficult to achieve
with many of the current technologies. In addition, extra precautions
must be taken to ensure the therapeutic gene does not integrate into
unwanted cell types. Gene silencing has to be done during earlier gene
transfer trials. This is to ensure the gene was effectively introduced into
the target cells and will not be just expressed for a limited length of time.
Special precautions must be taken if DNA is inserted into the cell
chromosome. The site of insertion must be in an area of the genome that
does not promote caner.
In May 2006 a team of scientists led by Dr. Luigi Naldini and Dr. Brian
Brown from the San Raffaele Telethon Institute for Gene Therapy (HSR-
TIGET) in Milan, Italy reported a breakthrough for gene therapy in which
they developed a way to prevent the immune system from rejecting a
newly delivered gene. This work will make the gene transfer for treating
colon cancer more promising.
Conclusion:
Gene therapy and Hepatic Arterial Infusion are the two promising new technologies that promises success in treating colorectal cancer (CRC).
HAI has been highly recommended for post resection of liver to treat colorectal cancer which has colonized the liver while Gene Therapy is the correction of the single
gene defect, which causes the disease phenotype. This is further enhanced with a breakthrough for gene therapy which prevents the immune system from rejecting
a newly delivered gene in the liver.
Both therapies have their advantages and limitations. HAI pumps are favorable with regard to its low undesirable side effects and increased survival period. The pump
permits direct delivery to catheter without disturbing the reservoir. Gene Therapy is risky as it has more limitations in the current development. Extra precautions
must be taken to ensure the therapeutic gene does not integrate into unwanted cell types. The insertional site must be in an area of the genome that does not
promote cancer if DNA is inserted into the chromosome.
In conclusion, both therapies offer benefits to the treatment of colorectal cancer. Treatment should be determined based on the aspects of the cancer as well as the
complications which the subject possesses.
Reference:
• Rein, D.T., Breidenbach, M., & Curiel, D.T., 2006. Current developments in adenovirus-based cancer gene therapy. Future oncology (London, England), 2(1): P137-143
• Cross D, Burmester J.K, Gene Therapy for Cancer Treatment: Past, Present and Future, Clin Med Res ,2006 September, 4(3): P218–227.
• Chung-Faye G.A, Kerr D.J, 2000. Innovative treatment fro colon cancer, BMJ,Volume 321,P1397-9
• Dunlop M.G,1997.Colorectal cancer,BMJ,Volume 314, ,P1882-5
• Cohen, AD & Kemeny, NE 2003, ‘ Original Paper: Hepatobiliary’, An Update on Hepatic Arterial Infusion Chemotherapy for Colorectal Cancer, vol.8, no.6, pp. 553-566.
• Center for Pancreatic and Biliary Diseases, 2002, ‘HEPATIC ARTERY INFUSION CHEMOTHERAPY (HAI)’, University of Southern California, viewed 22 April 2008.
• Gene therapy used successfully to treat cancer , Cited on 21 April 2008, http://news.sawf.org/Health/19739.aspx
Julieana Ibrahim, Kia Liang Heng, Meng Lu, Pey San Chua & Rui Yang