Abstract: Cancer Watch September 1998

Among the highlights in the September 1998 Cancer Watch issue are: Alkaline Phosphatase Isoenzymes in Breast Caner, Amifostine, Emerging New Roles, Accumulation of p53 Protein in Benign Breast Cancer Disease and Risk of Breast Cancer, A New Candidate Gene for Hormone-Resistant Prostate Cancer, A Novel Metastasis-Suppressor Gene Identified, Psoriasis Treatment and Risk of Skin Cancer, Skin Cancer Prevention Trial, Molecular Path to Colon Cancer, The Dosage of Anticancer Agents: Trials and Tribulations, Molecular Detection of Micrometastases in Colorectal Cancer, Anti-angiogenesis in Cancer with Marimastat – A Logical Strategy, Technology Update: Optical Coherence Tomography, A Small Molecule Mimics an Important Cytokine, Benign Prostatic Hyperplasia is Not a Precursor of Prostate Cancer, Vitamin D in Prostate Cancer, DNA - the Master Molecule: Chromatin-Remodeling Protein Involved in Carcinogenesis, New Cancer Genetic Network Launched by NCI and History of Nonmelanoma Skin Cancer Increases Cancer Mortality.

News in Brief

• Alkaline Phosphatase Isoenzymes in Breast Caner
• Amifostine, Emerging New Roles
• Accumulation of p53 Protein in Benign Breast Cancer Disease and Risk of Breast Cancer
• A New Candidate Gene for Hormone-Resistant Prostate Cancer
• A Novel Metastasis-Suppressor Gene Identified

• An exceptionally effective treatment for psoriasis, a common skin disease, is high dose oral psoralen along with UV exposure However, this treatment can increase the risk of non-melanoma skin cancer and hence should be given only to those patients who would benefit sufficiently and they should be monitored carefully even after the treatment is stopped.

• ILEX Oncology, Inc. is enrolling patients for a phase III trial of its anticancer agent alph-difluoromethylornithine (DFMO) for the prevention of non-melanoma skin cancer. This study, led by Paul Carbone, University of Wisconsin's Comprehensive Cancer Center and supported by the National Cancer Institute, represents the first phase III trial of DFMO as a chemoprevention agent to inhibit the recurrence of cancer. In this skin cancer prevention study 340 subjects will be selected with a history of either basal cell or squamous cell cancer. Low-dose drug versus placebo will be tested in a double blind randomized trial and the patients are expected to remain on the trial for an average of four years. The trial will assess DFMO's efficacy to inhibit the recurrence of cancer.

• The tumor suppressor gene adenomatous polyposis coli (APC), which is inactivated in most colorectal cancer is found to be involved in the activation of the oncogene c-MYC.

• Effective chemotherapeutic agents are destructive agents. Apart from the judicious (or lucky?) choice of an appropriate drug regime, a balance must be struck between successful cancer therapy and its deleterious effects, obviously by adjusting the optimal dosage. So far, this is being sought by various calculations, often based on empirical data from preliminary trials. Improvements in drug administration require novel approaches and flexible thinking; until we know more, it would be wise to avoid sweeping standardizations and uniform protocols. Certainly, there is no room for reductionism and a "one-dimensional approach".

• Micrometastasis, that is, presence of a very few cancerous cells, may not be detected by standard technique. These undetected cells in local lymph nodes of certain stage II colorectal cancer patients can cause recurrence of the disease because routinely adjuvant therapy is not given to them after surgical removal of the tumors; about 20% of stage II patients die of recurrent disease. Very sensitive molecular detection techniques can identify these subset of patients for adjuvant therapy.

• The logic seems perfect: a growing tumor requires oxygen and nutrients; to get both, cancer cells secrete substances that stimulate the growth of new vessels; if the blood supply can be impeded, the tumor should eventually starve, shrink and ultimately disappear, without further detriment to the host. This concept is not new – there are at least 300 substances which potentially inhibit angiogenesis under study. New, however, is the recent media hype which resulted in an unwarranted rise in the hopes of cancer patients (and some pharmaceutical equities!); both are equally premature. It is still a long, tortuous road to the production of angiostatin and endostatin in sufficient amounts for testing in statistically valid numbers of patients. A more indirect approach, using Marimastat as metalloproteinase inhibitor, is perhaps less "newsworthy", but of more immediate interest. At present, to quote Dr. Judah Folkman (one of the pioneers of the anti-angiogenic strategy): "If you have cancer and you are a mouse, we can take care of you".

• Optical coherence tomography is a new method that utilizes infrared light to image deep tissue structure in vivo and in real time without the need to biopsy specimen. This technique can identify cellular structure to a level comparable to conventional histological methods. Because no exogenous chemical agent is required to enhance the image, this procedure will not damage the tissue. This technique has potential for a wide variety of application including screening and diagnosis of precancerous and cancerous changes.

• A synthetic small nonprotein molecule activates a large receptor protein normally activated by a protein such as G-CSF that stimulates growth and differentiation of specific blood cells.

• Often it is feared that enlargement of prostate gland known as benign prostatic hyperplasia (BPH) may lead to cancer. Prostate cancer is one of those cancers that could grow very aggressively, or very slowly. Specific molecular markers for these diseases will be helpful to design treatment strategy. A protein product of the negative cell-cycle regulator gene p27 is found to play an important role in prostate disease. And the pattern of expression of this gene suggests that BPH and prostate cancer are distinct at the molecular level. Lower level of p27 protein in cancer patients is associated with biological aggressiveness.

• The steroids never ceases to surprise with their ambiguous and unpredictable effects in cancer, resulting from minute alterations in their configuration, side-chains and double bonds. The active vitamin D metabolite (calcitriol) and some of its analogs are antiproliferative and induce differentiation in several cancer cell lines. Gradually, the molecular mechanisms of these actions are being understood; the first clinical trials are underway.

• Protein complexes called chromatin-remodeling proteins bind to compact nucleosomes perturbing their conformation so that DNA will be accessible to other factors such as transcription factors for RNA synthesis. These are multiprotein complexes and are involved in transcription of key genes needed for growth, differentiation, or apoptotic processes. It is now believed that one of the small subunits of these protein complexes may function as tumor suppressor.

• A five-year pilot network to study cancer genetics has been launched by the National Cancer Institute. Several institutions will participate in this network and carry out interdisciplinary collaborative functions.

• History of nonmelanoma skin cancer increases the risk of dying from other cancers by 20 to 30 percent. Biological reasons for this heightened death risk is not clear.

Glossary

• A glossary of unfamiliar words and jargons in Cancer Watch, September 1998.