Serial transplants of DMBA-induced mammary tumors in Fischer rats as model system for human breast cancer. IV. Parallel changes of biopterin and melatonin indicate interactions between the pineal gland and cellular immunity in malignancy.

Nocturnal (23.00-07.00 h) urinary melatonin and total biopterin (tBI; after acidic oxidation of reduced biopterins) were analyzed during the growth of two passages of a mammary tumor line in female F344 Fischer rats. In addition, nocturnal (02.00-03.00 h) peak concentrations of pineal melatonin in plasma were analyzed when tumors had reached comparable average tumor volumes of 25-30 cm3. Since tetrahydrobiopterin (BH4) is produced by murine macrophages in response to interferon-gamma released by activated T lymphocytes, measurements of tBI can serve to estimate the state of cellular immunity. At passage 2, a slow-growing localized carcinosarcoma, tBI showed a progressing increase during tumor growth reaching more than 200% (p < 0.05-0.005) of controls by the end of the experiment. Urinary and plasma melatonin were elevated by 30-50% (p < 0.05) and 42% respectively. At passage 12, a fast-growing metastasizing sarcoma, a depression of about 20-30% was found for tBI (p < 0.05) and urinary melatonin (p < 0.025); plasma melatonin was depleted by 70% (p < 0.005). Parallel changes of both parameters at each tumor passage indicate a close link between the pineal hormone melatonin and cellular immunity. The opposite trends observed at the two passages indicate a clear stimulation of the immune system and the pineal gland at early but inhibition at advanced stages of cancer.

Increasing urinary levels of modified nucleosides and bases during tumor development in mice.

Based on the fact that human cancer patients excrete increased amounts of various modified nucleosides and bases in their urine, we investigated whether the same phenomenon takes place in mice bearing experimentally induced tumors. We did indeed find that mice with MCA-induced skin tumors and mice exhibiting leukemia after X-ray irradiation excrete severalfold higher levels of modified nucleosides and bases than do untreated control mice. Comparison of the time course of altered urinary excretion of these RNA catabolites with the appearance of a recognizable tumor after MCA application revealed that the onset of the altered excretion rate of these compounds precedes tumor diagnosis. At present, the time-course studies in our mice exposed to a single X-ray dose to induce lymphoblastic leukemia seem to indicate a similar situation. Mice exhibiting preleukemic histological features already excrete increased amounts of various modified nucleosides and bases. Confirmation of our results by analysis of further irradiation-exposed mice in our present detailed time-course studies and of tumors experimentally induced in other organs of mice and other species will be taken as a basis for developing an in vivo test for carcinogenicity. Furthermore, the results could provide a foundation for the setting up of a noninvasive, early screening method for cancer in human beings.

Urinary glycolipids of YC8 lymphoma bearing mice: effectors of glycosylation process.

Glycolipids from YC8 lymphoma bearing mice urines have peen obtained by the method of Folch and fractionated on silicic column and on silica gel plates. One fraction, among the five obtained, may be used by sera galactosyltransferase as an acceptor for galactose, to form a new glycolipid compound. Furthermore this fraction has shown an inhibitory effect on phosphatase activity, in agreement with hypothesis which relates relates glycosyltransferase and phosphatase activities during tumorous process.