Heavy water enhances the antineoplastic effect of 5‐fluoro‐uracil and bleomycin in nude mice bearing human carcinoma

Abstract

The antineoplastic effect of heavy water on the growth of xenotransplanted human carcinoma was compared to that of 2 cytostatic drugs. Seven-week-old BALB/c-nu/nu mice were inoculated subcutaneously with a poorly differentiated oropharyngeal squamous-cell carcinoma, or with variants of carcinoma of the large intestine. After tumor inoculation, 3 subgroups of mice were treated by: (i) moderately deuterated drinking water; (ii) i.p. injections of 5-Fluoro-uracil (5-FU) or Bleomycin; (iii) a combination of deuterated drinking water and of the cytostatic drugs. Control mice were not treated. Heavy water delayed growth of all carcinoma variants. The cytostatic drugs slowed down the growth of the 2 poorly differentiated tumor variants. Conversely, 5-FU did not retard the growth of the moderately well differentiated colon carcinoma. Heavy water combined with either cytostatic drug showed synergistic effects in the 2 poorly differentiated tumor variants. The tumors of treated animals weighed 36% to 90% less than those of control animals. The antineoplastic effects were more conspicuous in poorly than in moderately well differentiated tumor variants. Cytokinetic parameters such as labelling indices following application of 5-125I-Iodo-2'deoxyuridine, and of Ki-67, a monoclonal antibody (MAb) directed against an antigen of proliferating cells, or mitotic indices and tumor volume doubling time, combined with the results of histologic evaluation of the tumors, suggested an underlying deuterium-induced prolongation of tumor-cell cycle times and a reduction of the growth fraction.

SDZ PSC 833, A non‐immunosuppressive cyclosporine: Its potency in overcoming P‐glycoprotein‐mediated multidrug resistance of murine leukemia

“…Simultaneous application of oral PSC 833 enhanced the cytostatic activity and toxicity of adriamycin. This effect is not strain-dependent, since we have observed it in drug-sensitive human colon carcinoma xenografts on nude mice (Altermatt et al, 1990). The time between application of PSC 833 and adriamycin was set to 1 hr.…”

Paradoxical effects of bleomycin and heavy water (D2O) in mice

“…Animals of one sub-group received tap water (H20) during the whole experiment; the animals of the other sub-group drank deuterated water (D20; tap water with 30 v01.-% DZO) during the pre-injection period (PRIP, 12 days), the injection period (IP, 32 days) and the post-injection period (POIP, 7 days, Table I). The deuterated water was prepared as described (Altermatt et al, 1990). During the ACP (5 days) and the final period (FP, 15 days, Table I) all animals drank tap water.…”

“…Moderate deuteration of body fluids by ingestion of heavy water may retard growth of transplantable tumors (Altermatt et al, 1990). The mechanisms mediating retardation of normal and neoplastic cell proliferation by heavy water are largely unknown.…”

“…The mechanisms mediating retardation of normal and neoplastic cell proliferation by heavy water are largely unknown. Cytokinetic parameters, mitotic indices and tumorvolume doubling time suggest that deuterium may result in prolongated cell-cycle times and a reduced growth fraction (Altermatt et al, 1990). Further, heavy water is immunosuppressive and leads to lymphocytopenia (Laissue and Stoner, 1979).…”

Heavy Water Reduces GFP Expression in Prokaryotic Cell-Free Assays at the Translation Level While Stimulating Its Transcription

“…While deuterium oxide at concentrations greater than 20% of body weight is highly toxic to animals [13], low concentrations of deuterium oxide seem to be harmless for animals and humans, and deuterated intraocular dyes are considered to be safe for clinical use [14]. Furthermore, several studies provided evidence for a significant reduction of human cancer cell lines growth in D 2 O culture medium [15], impairment of human tumor growth in animal models [16, 17], and generally a reduction of cellular proliferation at high deuterium concentrations in prokaryotic and eukaryotic cells [16, 18, 19]. …”