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 techniqueA 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. 1In 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