F J E Gardner, J C Konje, et al ( Department of Obstetrics and Gynaecology and Epidemiology and Public Health, University of Leicester, UK and Department of Histopathology and Clinical Oncology, Leicester, UK)
Endometrial protection from tamoxifen-stimulated changes by a levonorgestrel- releasing intrauterine system: a randomised controlled trial.
The Lancet, vol.356, November 18, 2000, pg. 1711-17.
Tamoxifen is the most commonly used adjuvant treatment for breast cancer, but it frequently causes uterine bleeding which could be associated with proliferative changes of the endometrium or endometrial cancer. This study has assessed whether a levonorgestrel intrauterine system could modulate the uterine responses to tamxoifen and tolerance of insertion, removal and potential side-effects of the device.
This was a randomized controlled trial (n=122) in which post-menopausal women who had at least 1yr of adjuvant tamoxifen treatment were randomly assigned to either endometrial surveillance alone or endometrial surveillance before and after insertion of the levonorgestrel IUD for 12 months. Tolerance of the surveillance procedure and the device was by using visual analogue scales.
The finding of the study was that the levonorgestrel – releasing IUD system had a protective action against the uterine effect of tamoxifen.
- Manel Esteller, Jesus Garcia Foncillas et al
Inactivation of the DNA repair gene MGMT and the clinical response of gliomas to alkylating agents.
New Eng J Med. Vol.343, Nov.9, 2000,pg.1350.
Summary: The DNA repair enzyme O6-methyl-guanine-DNA methyltransferase (MGMT) inhibits the killing of tumour cells by alkylating agents. MGMT activity is controlled by a promoter and methylation of the promoter silences the gene in cancer and the cells no longer produce MGMT. Authors examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumour to alkylating agents.
MGMT promoter in tumour DNA was analysed by a specific PCR assay. Gliomas were obtained from patients treated with carmustine. Molecular data were correlated with the clinical outcome. MGMT promoter was methylated in 40% of gliomas and this was associated with regression of the tumour and prolonged overall and disease free survival. It was an independent and stronger prognostic factor than age, stage, tumour grade or performance status.
The conclusion was that methylation of the MGMT promoter in gliomas is a useful predictor of responsiveness of the tumours to alkylating agents.
Editorial : John N Weinsten, pg.1408
Pharmacogenomics – Teaching old drugs new tricks.
Summary: Traditionally, cancer treatments have been selected on the basis of tumour type, pathological features, clinical stage, the patient’s age and performance status and other nonmolecular considerations. The field of pharmacogenomics, through the study of large number of genes that influence drug activity, toxicity and metabolism, provides the opportunity to tailor drug treatments and to eliminate many of the uncertainties of current therapy for cancer.
Strong support for this concept is provided by the study of genetic polymorphisms that influence drug metabolism. CYP2D6 affects metabolism of several drugs (beta-blockers, antidepressants, antipsychotics and opioids). Dihydropyrimidine dehydrogenase influences metabolism and therefore neurotoxicity of fluorouracil.
Esteller and colleagues provide clinical evidence to explain the resistance of some gliomas to nitrosourea alkylating agents. Carmustine and other nitrosoureas kill by alkylating O6 position of guanine and thereby cross-linking adjacent strands of DNA. Formation of these cross-links can be prevented by MGMT, which rapidly reverses alkylation. About 30% of gliomas lack MGMT. A lack of MGMT appears to correlate with sensitivity to carmustine. Methylation of MGMT promoter could be used to predict responses to treatment with carmustine.
Pharmacogenomics studies will produce benefits both for clinical research and standard practice. Potential advantages include discovery of better drugs, elimination of poor candidates early in the development process, and dramatic decrease in size and expense of clinical trials.
- Scott Gottlieb, New York
Cancer drug may cause heart failure
BMJ, Vol.321, July 29, 2000, pg.259.
Trastuzumab (Herceptin) is a monoclonal antibody that binds to a protein found on the surface of some cells. The protein, HER2, helps to regulate cell growth. By binding to tumour cells, trastuzumab inhibits growth of cancerous cells. It is currently approved for use in metastatic breast cancer.
Editorial in ‘Circulation’ has reported that heart failure occurs in 7% of women taking trastuzumab alone and this rate increases to 28% in women taking the drug with other chemotherapy drugs.
A team of researchers is calling for long-term studies investigating the risk of heart failure among women taking trastuzumab.