Therapeutic opportunities from tumour biology in metastatic colon cancer

doi:10.1016/S0959-8049(00)00150-7

European Journal of Cancer

Volume 36, Issue 13, August 2000, Pages 1706-1712

https://doi.org/10.1016/S0959-8049(00)00150-7 Get rights and content

Abstract

Tumour metastasis is the major cause of morbidity and mortality from colorectal cancer. While improvements in quality of life and patient survival have been made over the past 10 years, the majority of patients with metastatic colorectal cancer will die from their disease. As knowledge of the biology of colon cancer and its invasion/metastasis programme evolve, this presents new therapeutic opportunities for pharmacological and genetic intervention. This review discusses the current approaches to metastatic colorectal cancer therapy, details genomic and biological variance between primary and metastatic tumours, and highlights approaches for harnessing these differences to improve therapy.

Section snippets

The clinical problem

Colorectal cancer is a common disease in all the developed nations of the world [1]. It ranks second in incidence to lung cancer in men and breast cancer in women. Since it is a disease of the elderly it is predicted to become even more prevalent in the ageing population. Colon cancer is equally common in men and women, but men predominate in rectal cancer incidence, for reasons that are presently unclear.

Unfortunately, the early symptoms of colorectal cancer may be unspecific or non-existent.

Metastases are not biologically or genetically identical to primary tumours

While therapy used in the treatment of metastatic colon cancer is targeted towards secondary lesions, often little is known of the biological make-up of metastatic deposits. In general, markers of prognosis or response are assessed in the context of the primary tumour, with the assumption that this reflects the situation in the secondary disease. This is often due to a lack of availability of tissue from metastatic lesions, as such biopsies are technically difficult to obtain and are associated

Enlightened biology to generate enlightened therapy

It is time for genomic and biological approaches which have the specific aim of identifying new targets for treating metastatic disease. The data from the two CGH studies in metastatic colon cancer identify loss of chromosome 22q as a high frequency event (Table 2), when compared with primary tumour 11, 12. Using data from both papers, loss of this chromosome arm was observed in 10/17 liver metastases and 3/22 primary tumours. With complete sequence analysis of chromosome 22 recently completed

Concluding comments

New targets are clearly needed for curative therapies to be developed for metastatic colorectal cancer. Taking advantage of current biological differences in secondary metastasis and expanding this knowledge to a more comprehensive level, offers the best hope of achieving this goal. Using biological findings to develop therapy is not a novel concept. In the 1950s, 5-FU was developed from the observation that tumours have greater uracil utilisation than normal tissues [44]. Similar rationale

Acknowledgments

Research in the Author's laboratory is supported by Scottish Hospitals Endowments Research Trust, The Dr James A. Mearns Trust, and the Aberdeen Colorectal Initiative.

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Therapeutic opportunities from tumour biology in metastatic colon cancer

Abstract

Section snippets

The clinical problem

Metastases are not biologically or genetically identical to primary tumours

Enlightened biology to generate enlightened therapy

Concluding comments

Acknowledgments

Ann. Oncol.

Tumour markers of prognosis in colorectal cancer

Br. J. Cancer

Patterns of recurrence following curative resection of adenocarcinoma of the colon and rectum

Cancer

An international, multidisciplinary approach to the management of advanced colorectal cancer

Anticancer Drugs

Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer

N. Engl. J. Med.

Hepatic arterial chemotherapy in metastatic colorectal patients

Semin. Oncol.

A review of the pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer

Br. J. Clin. Pharmacol.

Liver resection for colorectal metastases

J. Clin. Oncol.

Surgery for lung metastases from colorectal canceranalysis of prognostic factors

J. Clin. Oncol.

Repeated liver resection for recurrent liver cancer

Br. J. Surgery

Analysis of colorectal cancer by comparative genomic hybridizationevidence for induction of the metastatic phenotype by loss of tumor suppressor genes

Clin. Cancer Res.

Comparative genomic hybridization analysis of primary colorectal carcinomas and their synchronous metastases

Genes, Chrom. Cancer

Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors

Cancer Res.

Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin

J. Clin. Oncol.

Lack of correlation between thymidylate synthase levels in primary colorectal tumours and subsequent response to chemotherapy

Br. J. Cancer

Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma

J. Clin. Oncol.

Thymidylate synthase protein expression in advanced colon cancercorrelation with the site of metastasis and the clinical response to leucovorin-modulated bolus 5-fluorouracil

Clin. Cancer Res.

Response to fluorouracil therapy in cancer patientsthe role of tumoral dihydropyrimidine dehydrogenase activity

J. Clin. Oncol.

Regulation of dihydropyrimidine dehydrogenase in colorectal cancer

Clin. Cancer Res.

Expression of cell cycle control proteins in primary colorectal tumors does not always predict expression in lymph node metastases

Clin. Cancer Res.

The DNA sequence of human chromosome 22

Nature

Gene therapy for colon cancer

Hematol. Oncol. Clin. N. Am.