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Tumor prevention by 9-cis-retinoic acid in the N-nitroso-N-methylurea model of mammary carcinogenesis is potentiated by the pineal hormone melatonin.

Abstract
Our laboratory has demonstrated that treatment of MCF-7 breast cancer cells with melatonin (Mlt) followed 24h later with physiological concentrations of all-trans retinoic acid (atRA) results in apoptosis. These studies were extended into trials using the N-nitroso-N-methylurea (NMU)-induced rat mammary tumor model. Initial studies conducted by feeding the animals 9-cis-retinoic acid (9cRA in the chow) and administering melatonin by subcutaneous injection in the late afternoon demonstrated that the combination of Mlt and 9cRA was able to significantly prevent tumor development, and that the combination was more efficacious that either Mlt or 9cRA alone. In this report, we conducted studies to determine if lower doses of 9cRA could be used in combination with Mlt while still maintaining anti-tumor activity and if the route of administration of 9cRA (bolus (gavage) v.s. chronic (chow) routes) affected its interaction with Mlt. The studies presented here demonstrate that significantly reduced doses of 9cRA can be used in combination with Mlt while maintaining anti-tumor efficacy. Furthermore, our studies demonstrate that 9cRA is equally effective when it is administered chronically (chow) or as a bolus (gavage). These data demonstrate that the combined use of Mlt and 9cRA produces additive or synergistic effects, which are more efficacious than 9cRA alone. This combination of Mlt and 9cRA could be a potentially useful clinical treatment regimen for breast cancer since it allows the use of lower doses of retinoic acid, thus, avoiding the toxic side effects associated with the use of high dose retinoids.
AuthorsS Nowfar, S R Teplitzky, K Melancon, T L Kiefer, Q Cheng, P D Dwived, E D Bischoff, K Moro, M B Anderson, J Dai, L Lai, L Yuan, S M Hill
JournalBreast cancer research and treatment (Breast Cancer Res Treat) Vol. 72 Issue 1 Pg. 33-43 (Mar 2002) ISSN: 0167-6806 [Print] Netherlands
PMID12004806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Alitretinoin
  • Tretinoin
  • Methylnitrosourea
  • Melatonin
Topics
  • Administration, Oral
  • Alitretinoin
  • Animals
  • Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Breast Neoplasms (drug therapy)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Female
  • Injections, Subcutaneous
  • Mammary Neoplasms, Experimental (chemically induced, pathology, prevention & control)
  • Melatonin (administration & dosage, pharmacology, therapeutic use)
  • Methylnitrosourea
  • Rats
  • Rats, Sprague-Dawley
  • Tretinoin (administration & dosage, pharmacology, therapeutic use)

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