NEW YORK (Reuters Health) - Markers of cell proliferation in breast tumors are decreased following percutaneous application of 4-hydroxytamoxifen (4-OHT), French researchers report. The reduction over 2 to 3 weeks of use is of the same order of magnitude as that induced by oral tamoxifen.
Though effective as a chemopreventive agent or as adjuvant therapy, tamoxifen is associated with significant adverse effects. The most active metabolite of tamoxifen, 4-OHT used as a topical agent has yielded promising results, lead investigator Dr. Philippe Rouanet and his research team report in the May 1st issue of the Journal of Clinical Oncology.
Dr. Rouanet, from the Centre Val d’Aurelle in Montpellier, and his associates enrolled 49 postmenopausal women with breast cancer who had undergone tumor biopsy and were scheduled for tumor resection surgery.
Prior to surgery, patients were randomly assigned to topical 4-OHT (0.5 mg, 1 mg or 2 mg) applied to each breast daily; oral tamoxifen 20 mg/day; or no treatment for 15 to 22 days. Tissue was evaluated at the time of biopsy and resection for labeling indices of proliferating cell nuclear antigen (PCNA) and Ki-67 antigen, and estrogen and progesterone receptors.
Active treatment with either drug resulted in significant reductions in labeling indices of PCNA (p = 0.002) and Ki-67 (p = 0.0055) in tumor tissue, while markers increased in control subjects. Estrogen receptor concentrations decreased as well with both 4-OHT and tamoxifen (p = 0.012).
There were no discernible effects of either drug on apoptosis as measured by percentage tumor tissue TUNEL and Bcl-2.
Tumor 4-OHT concentration was 4237 pg/g in the oral tamoxifen group and 687, 1377 and 1698 pg/g in the three ascending dose groups of the percutaneous drug. Plasma concentrations were 1495 pg/mL in the tamoxifen group versus 31, 35, and 164 pg/mL in the 4-OGT groups.
Five patients in the 4-OHT arms and two in the tamoxifen arm reported hot flushes, but the investigators could not tell whether they were due to the drugs or their postmenopausal state.
Summing up, the authors write, “The group receiving 2 mg of percutaneous 4-OHT showed the same cytostatic effect on breast cancer cell proliferation as the oral tamoxifen group, despite markedly lower plasma 4-OHT concentrations. This finding suggests that a major effect of tamoxifen is locally mediated by ERs in breast tumor tissue.”
They conclude that “4-OHT gel can be an efficient method to control mammary cell proliferation, with no systemic effect.”
Source: J Clin Oncol 2005;23:2980-2987. [ Google search on this article ]
MeSH Headings:Biological Factors: Immunologic and Biological Factors: Nuclear Proteins: Receptors, Estrogen: Receptors, Progesterone: Receptors, Steroid: Transcription Factors: Tumor Markers, Biological: Biological Markers: Drugs, Investigational: Receptors, Cytoplasmic and Nuclear: Proliferating Cell Nuclear Antigen: Genes, bcl-2: Ki-67 Antigen: Chemical Actions and Uses: Chemical Actions: Chemicals and DrugsCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
