Effects of Olfactory Bulbectomy, Melatonin, and/or Pinealectomy on Three Sublines of the Dunning R3327 Rat Prostatic Adenocarcinoma

Abstract

Conventional antiandrogen therapy for prostatic cancer generally results in the death of androgen-dependent cells, resulting in shrinkage of the tumor, followed by regrowth of the tumor as androgen-insensitive cells take over. Because of reported antigonadotropic and antineoplastic effects of the pineal hormone melatonin (MEL), we hypothesized that this indole might provide an effective therapy for prostate cancer, as it would be effective against both populations of tumor cells. We used three sublines of the Dunning R3327 rat prostatic adenocarcinoma to determine whether MEL could suppress the growth of these tumors and, if so, by what mechanisms this occurs. In one experiments, we compared the growth of a well-differentiated slow-growing Dunning tumor in rats given MEL combined with the potentiating procedure olfactory bulbectomy (BULBX), with that in rats pinealectomized (PINX) or untreated. Tumor growth in BULBX-MEL rats was significantly suppressed over that in the other two groups, as were the weights of the gonads and accessory sex glands. Tumor morphology, DNA concentration, and androgen receptor concentration and distribution were identical in untreated controls and in BULBX-MEL rats, suggesting that the treatment affected all populations of tumor cells equally. With another strain of well-differentiated slow-growing Dunning tumor, we examined the effects of MEL in rats with and without BULBX. Reproductive parameters were not suppressed in BULBX-MEL rats and, while there was a trend toward slower tumor growth in this group, this was not significant. Intact rats given MEL grew larger tumors than did control rats but, again, differences were not significant. In a third experiment, we examined a fast-growing androgen-insensitive anaplastic Dunning tumor. PINX was without effect on this tumor, but BULBX-MEL resulted in a significant suppression of one of the constants in the logistic equation fitted to the growth curves. This indicates that there were some direct antitumor effects of BULBX-MEL on this tumor strain. We conclude that MEL suppresses growth of some Dunning tumor strains.

WOMEN IN CANCER THEMATIC REVIEW: Circadian rhythmicity and the influence of ‘clock’ genes on prostate cancer

“…Comparison of serum levels of melatonin in elderly men with benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), and localized CaP, as well as in normal adult men without CaP, demonstrated that melatonin induced significant circadian rhythms in normal men and patients with benign prostatic hyperplasia (BPH) (enlarged prostate) and prostatic intraepithelial neoplasia (PIN) (considered to be a precursor for prostate cancer) but not in patients with CaP (Bartsch, et al 1985). In support of these reports, a rodent model affirmed that melatonin suppresses prostate tumorigenesis (Toma, et al 1987). …”

Studies on the effects of the pineal hormone melatonin on an androgen-insensitive rat prostatic adenocarcinoma, the Dunning R 3327 HIF tumor

“…We have previously reported on the effects of melatonin on three sublines of a rat prostatic adenocarcinoma model, the Dunning R 3327 tumor (Toma et al, 1987). In one slow-growing well-differentiated subline, we found that melatonin markedly inhibited tumor growth in anosmic rats.…”

“…In an earlier report (Toma et al, 1987), we showed that melatonin injections 132 G.R. Buzzell can slow the growth of some sublines of the Dunning R 3327 rat prostatic adenocarcinoma but that these effects are variable.…”

“…Tumors were measured weekly in a manner which has been descirbed (Toma et al, 1987). Briefly, tumors were measured with calipers in 3 directions, and volumes were calculated from the formula of an ellypsoid, after subtracting 1.3 mm from each measurement for the double skin thickness.…”

“…The pineal hormone melatonin has been shown to suppress tumor growth in a number of experimental systems, including mammary tumors (Tamarkin et al, 1981;Shah et al, 1984), prostate tumors (Toma et al, 1987), and melanomas (Stanberry et al, 1983). Since growth of these tumors is affected by host estrogens or androgens, whose secretion is influenced by melatonin, the question has arisen of whether melatonin has direct antitumor actions or whether it owes its effects on tumors to its actions on other host hormones.…”