Alternative Colon Cancer Treatment

There are a number of colon cancer patients who have had very good results using Immuno-Augmentive Therapy.

For very advanced colon cancer a combination of therapies has resulted in some of the best results we have seen.

A typical combination program includes immune therapy, intravenous vitamin C, angiogenesis inhibitors and 5FU/leucovorin chemotherapy.

Below are abstracts of articles supporting the logic of using these therapies. Also see Clinical and Experimental Experiences with Intravenous Vitamin C.

IMMUNE THERAPY

Morse MA, Nair SK, Mosca PJ, Hobeika AC, Clay TM, Deng Y, Boczkowski D, Proia A, Neidzwiecki D, Clavien PA, Hurwitz HI, Schlom J, Gilboa E, Lyerly HK. Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA. Cancer Invest. 2003 Jun;21(3):341-9. Department of Medicine, Medical Center, Box 3233, Durham, North Carolina 27710, USA. m.morse@cgct.duke.edu

Immunizations with dendritic cells (DC) transfected with RNA encoding tumor antigens induce potent tumor antigen-specific immune responses in vitro and in murine models. We performed a phase I study of patients with advanced carcinoembryonic antigen (CEA)-expressing malignancies followed by a phase II study of patients with resected hepatic metastases of colon cancer to assess safety and feasibility of administering autologous DC loaded with CEA mRNA. The immunizations were well tolerated. Of the 24 evaluable patients in the dose-escalation phase, there was 1 complete response (by tumor marker), 2 minor responses, 3 with stable disease, and 18 with progressive disease. In the phase II study, 9 of 13 patients have relapsed at a median of 122 days. Evidence of an immunologic response was demonstrated in biopsies of DC injection sites and peripheral blood of selected patients. We conclude that it is feasible and safe to administer mRNA-loaded DC to patients with advanced malignancies.

Dalerba P, Maccalli C, Casati C, Castelli C, Parmiani G. Immunology and immunotherapy of colorectal cancer. Crit Rev Oncol Hematol. 2003 Apr;46(1):33-57. Unit of Immunotherapy of Human Tumours, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milan, Italy.

This review critically discusses data on immunology of colorectal cancer, starting from pathology and molecular biology, and then considering the molecular characterisation of colon cancer antigens and the clinical trials of immunotherapy. A careful evaluation of histopathological studies on intra-epithelial infiltration by T cells in primary tumours, together with the analysis of HLA expression by colorectal cancer cells, suggest that anti-tumour T cell immune responses may take place in vivo in those patients, influencing prognosis and shaping the tumour immunological profile. Moreover, the molecular characterisation of tumour antigens expressed by colorectal carcinomas, together with improved understanding of mechanisms of the immune response and more sensitive methods for the in vivo detection of T cell responses, are now allowing researchers to design new and more effective vaccination protocols, with encouraging preliminary results. By drawing together the experimental evidence from different research fields, this review provides support for the concept that colorectal carcinoma is immunogenic and may reasonably be considered as a target for immunotherapy, and attempts to address critical issues and envisage future developments in this challenging research field.

ANGIOGENESIS INHIBITION

Thursday, February 26, 2004 Posted: 3:46 PM EST (2046 GMT)

WASHINGTON (AP) -- The government on Thursday approved the first drug that promises to attack cancer by choking off its blood supply, a colon cancer treatment called Avastin. www.CNN.com

The drug has only a modest benefit -- it can extend the lives of patients with advanced colon cancer by about five months, the Food and Drug Administration cautioned.

But it's a significant development, because Avastin becomes the first drug proved to work according to a novel theory that tumors must form a network of blood vessels to survive -- and that shutting down that process, called angiogenesis, could fight cancer in a manner completely differently than other treatments.

That theory was pioneered by Harvard University's Dr. Judah Folkman, who made front-page news in 1998 with reports that his anti-angiogenesis drugs had cured mice of cancer. But attempt after attempt to make such drugs work in people failed.

Indeed, the maker of Avastin, Genentech Inc., saw its stock plummet as recently as 2002 when the drug failed to help breast cancer patients.

Then doctors tried Avastin in the sickest of colon cancer patients, those whose cancer has spread to other parts of the body.

In a study of 800 people, half received intravenous Avastin in addition to routine chemotherapy. Not only was tumor growth delayed in those getting Avastin, but the Avastin patients lived about 20 months, five months longer than those getting standard treatment.

In patients that sick, even such a small benefit is considered medically important.

It also marked the first time in three decades of research that an anti-angiogenesis drug was proven to help people.

Avastin is a monoclonal antibody, a substance that seeks out and binds to one of the more 20 chemicals known to help tumors' blood vessels grow. The one Avastin targets is called vascular endothelial growth factor, or VEGF. When Avastin binds to it, VEGF can't stimulate blood vessel growth, thus keeping tumors from growing by denying them nourishing blood.

Avastin occasionally causes some serious side effects, the FDA cautioned. They include formation of holes in the colon that may require surgery to fix, impaired wound healing and internal bleeding.

More common side effects are high blood pressure, fatigue, blood clots, diarrhea, appetite loss and increased risk of infection because of decreased white blood cells.

Note: COX-2 inhibitors are medications that are readily available. Examples are Celebrex and Vioxx. VEGF is an active promoter of angiogenesis, or new blood vessel growth-required for tumors to grow.

The potential for a selective cyclooxygenase-2 inhibitor in the prevention of liver metastasis in human colorectal cancer. Yamauchi T, Watanabe M, Hasegawa H, Nishibori H, Ishii Y, Tatematsu H, Yamamoto K, Kubota T, Kitajima M. Anticancer Res. 2003 Jan-Feb;23(1A):245-9. Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

In a previous report we noted that cyclooxygenase-2 (COX-2) expression in clinical colorectal cancer is closely related to liver metastasis and survival. The aim of the present study was to clarify the role of COX-2 in liver metastasis and to examine the potential for a selective COX-2 inhibitor as a novel therapeutic agent in the treatment of colorectal cancer. MATERIALS AND METHODS: COX-2 expression of 6 kinds of human colon cancer cell lines, with various potentials for liver metastasis, were assessed by Western blot and reverse transcriptase polymerase chain reaction (RT-PCR). In human tumor xenografts/severe combined immune-deficient (SCID) mouse, we examined the effects of a selective COX-2 inhibitor (JTE-522) on tumor growth or liver metastasis of HT-29, a highly-metastatic cell line, or on COLO205, a non-metastatic cell line. The effect of JTE-522 on vascular endothelial growth factor (VEGF) expression and the activity of matrix metalloproteinases (MMPs) in HT-29 and COLO205 were assessed by enzyme-linked immunosorbent assay (ELISA) and gelatin zymography, respectively. RESULTS: COX-2 was expressed in all metastatic cell lines but not in the non-metastatic lines. JTE-522 prevented the liver metastasis of HT-29, but not the subcutaneous growth of HT-29 and COLO205 in SCID mice. In vitro, JTE-522 suppressed VEGF expression, but did not affect MMP production in HT-29; an inhibitory effect was not found in COLO205. CONCLUSION: A selective COX-2 inhibitor of JTE-522, was found to prevent liver metastases of colon cancer by suppressing VEGF expression, and therefore, COX-2 possibly plays an important role in liver metastasis of human colon cancer via the regulation of VEGF expression.