Sprague-Dawley rats bearing 7,12-dimethylbenz[a]
anthracene (DMBA)-induced mammary
tumors were treated with either of two aromatic
alkylating agents,
aniline mustard or
melphalan, alone or combined with
ovariectomy. Both drugs were applied once a week for 8 weeks. Eight-four percent of the
tumors responded to
ovariectomy, 38% regressing completely and 46% regressing partially.
Aniline mustard, though virtually ineffective as a single agent, appeared synergistic with
ovariectomy: a 100% regression rate (72% complete, 28% partial) was observed for this combination. Treatment with
melphalan was as effective as
ovariectomy, but the combination of
melphalan with
ovariectomy was no more effective than either treatment alone. The end product of
aniline mustard metabolism, p-
hydroxyaniline mustard O-
glucuronide, may be more extensively activated by
beta-glucuronidase in hormonally regressing than in growing or stationary
tumors. Intratumoral levels of beta-glucoronidase occurring in DMBA-induced
tumors 4 days after
ovariectomy were found to be similar to those in the
aniline mustard-sensitive mouse
plasma cell tumor ADJ/
PC6. It remains to be more extensively studied whether an effect of endocrine treatment on
tumor beta-glucuronidase levels, and possibly on intracellular distribution of
enzyme, could be used therapeutically. An effectively scheduled
cytostatic treatment (with a
drug conjugate such as that formed metabolically from
aniline mustard) in conjunction with
ovariectomy might be effective in the treatment of
hormone-responsive
breast cancer.