Among the highlights in the July 1999 Cancer Watch issue are: Reversion of Tamoxifen Resistance, Aromatase Inhibitors as Cancer Preventing Agents, Serum Interleukin-6 Metastatic Breast Cancer, The CA 242 Tumor Antigen in Colorectal Cancer, Juan del Regato, M.D., Pioneer in Cancer Treatment Dies at the Age of 90, Cancer Chemoprevention by Oltipraz, Chemotherapy for Renal Cell Carcinoma, Counseling for Women with Inherited Susceptibility to Breast Cancer, Non-Surgical Ablation of Liver Tumor, Sequential Endometrial Biopsy: Limited Value, High-Mobility-Group Proteins and Cisplatin Action, p73 in Cisplatin-Induced Cytotoxicity, Novel Germline Mutations in DNA Mismatch Repair Gene in African Americans, NCI Launches New Pediatric Brain Tumor Consortium, September 1999: Gynecologic Cancer Awareness Month, Gene Therapy: A Sober Update and Outpatient Biochemotherapy In Metastatic Malignant Melanoma .

• Reversion of Tamoxifen Resistance
• Aromatase Inhibitors as Cancer Preventing Agents
• Serum Interleukin-6 Metastatic Breast Cancer
• The CA 242 Tumor Antigen in Colorectal Cancer

• Juan del Regato, M.D., a pioneer in radiation therapy who developed programs to ensure quality cancer care practiced by qualified physicians died on June 12. Dr. del Regato also was a pioneer in treating inoperable prostate cancer with radiation therapy.

• Oltipraz, a substituted 1,2-dithiole-3-thione, was originally introduced in the treatment of schistosomiasis in the l980s. Because of numerous unpleasant side-effects as well as undesirable, dangerous photosensitivity, the use of the drug was abandoned. Less expensive, equi-effective and better tolerated substances (such as praziquantel) eventually replaced it, but while studying its mechanisms of action, markedly elevated glutathione levels in many tissues were noted. Subsequent studies clearly showed that oltipraz and related thiones are potent inducers of enzymes active in the maintenance of reduced glutathione pools and of other enzymes involved in electrophile detoxification: these observations stirred hopes that oltipraz may be useful as a non-specific, chemopreventive tool.

• Approximately 10.000 deaths annually can be attributed to adenocarcinomas of the kidneys in the US; the incidence is increasing at 2% yearly. Most renal cell carcinomas (RCC) are chemotherapy-resistant and exhibit only marginal response rates at best. Neither surgical intervention nor systemic treatment modalities (including multidrug-resistance modulators) have demonstrable survival benefits; one third of the patients have metastatic or locally advanced disease at presentation. The rationale for external radiation therapy remains controversial; contemporary techniques have decreased complication rates, but the indications are mainly palliative. Recently, more optimistic results with a combination "biochemotherapy" have been reported, consisting of interleukins, interferons and 5-fluorouracil.

• As it has happened in so many life science fields, technical advances (such as the Human Genome Project) outpaced by far our ability to adjust our ethical standards and the necessary legal limits, within which we can live comfortably. The "social response" to the exponential growth in our understanding of genetics is polarized: enthusiastic by some, hostile by others. There is danger both in overcautious and restrictive measures imposed by the lay – influenced by mostly incorrect or only partially correct media information – and in the boundless optimism of scientists who embark on genetic diagnostics in the hope to improve patient care. The identification of germline susceptibility genes and the recognition of their impact on oncogenesis – probably much greater than environmental factors – allows for increasingly accurate estimates on familial cancer risk. Breast cancer is a case in point.

• A new technique that generates heat by radio-frequency is used to destroy inoperable liver tumors. The procedure is simple, requires one treatment for most patients and is well tolerated.

• Breast cancer patients on tamoxifen therapy incur higher risk of developing endometrial cancer. Rates from the NSABP (B-14) trial were 0.2 cases of endometrial cancer per 1,000 women per year in the placebo arm, and in the tamoxifen arm 1.6 cases of endometrial cancer per 1,000 women per year. Richard R. Barakat, assistant attending surgeon, Memorial Sloan-Kettering Gynecology Service, presented data at a recent meeting of ASCO from a seven-year prospective Breast Service study looking at the effect of tamoxifen on the endometrium in women with breast cancer.

• Platinum compounds are very effective anticancer agents. It damages DNA mainly by crosslinking two adjacent purine bases in the same strand. The effectiveness of this agent can be reduced by endogenous repairing systems. An intracellular specific protein can recognize the platinated complex and bind to it providing a shield against the repairing systems. Precise interaction of such a protein at the molecular level is investigated.

• Cisplatin, an effective anticancer agent may cause cell death in several ways. One pathway is the activation of apoptosis by the damaged DNA from the covalent adduct with the drug. The tumor-suppressor protein p53 is an important factor in drug-mediated apoptosis. Other apoptotic pathways involving p73 gene product that requires the presence of c-Abl tyrosine kinase and an intact DNA mismatch repair system are also present in cisplatin-induced apoptosis.

• Novel mutations in DNA mismatch genes are detected in colorectal cancer-prone African American population. This suggests an association between these mutations and predisposition to colorectal cancer. Screening for these mutations can be used to facilitate surveillance to those at high risk.

• The National Cancer Institute (NCI) announced on April 5, 1999 that it has awarded funds for a Pediatric Brain Tumor Consortium, a network of medical centers that will evaluate promising treatments for children with brain cancers. The consortium is intended to speed up the development of innovative, technically challenging therapies.

• The Gynecologic Cancer Foundation along with American Hospital Association has declared September 1999 as the first annual Gynecologic Cancer Awareness Month.

• Efforts to sequence the human genome are accelerating, with scientists in the USA and UK aiming at a complete, "rough draft" by spring 2000 – a year earlier than anticipated. From further extensive cooperation, a final, high-quality sequencing is expected by 2003 at the latest. At least 90% of the Human Genome Project will be publicly available to the international scientific community and is seen as vital to the understanding of the very basis of life, health and disease. Over the past ten years, there have been almost daily reports about new genes that contribute to one disease or another; some are widely, but incorrectly publicized, raise false hopes and when preliminary trials fail, lead to the general impression that gene therapy can not – now or ever – fulfil our expectations. From time to time, it may be useful to look back, review the state of the art and explore new approaches.

• Over the past few years oncologists have been exploring various biochemotherapy regimens in an attempt to stem the usually rapid downward course of metastatic malignant melanoma (MMM). Regimens have usually combined interleukin-2 (IL-2) biotherapy, frequently adding interferon. The toxicity of these regimens combining chemotherapy with biotherapy has generally required inpatient management.

Glossary

• A glossary of unfamiliar words and jargons in Cancer Watch, July 1999.