Tumor cytokinetic effects of acute starvation versus polyamine depletion in tumor‐bearing mice

Abstract

Previous investigations in our laboratory have demonstrated that both acute host starvation and polyamine depletion by means of the irreversible ODC-inhibitor (ODC = ornithine-decarboxylase) fluoro-methylornithine (DFMO) lead to pronounced growth retardation of rapidly proliferating tumors. The aim of this investigation was to elucidate how these different interventions affect cell kinetics and cell cycle phases in vivo. Adult nongrowing mice (C57Bl/J) bearing a poorly differentiated rapidly growing methylcholanthrene induced sarcoma were used. Combined measurements of bromodeoxyuridine incorporation into DNA and flow cytometric techniques were used. Starvation and DFMO treatment resulted in a prolonged cell cycle transit compared to freely fed animals. Tumor cells from DFMO-treated mice demonstrated an increased time for DNA synthesis and a relatively larger accumulation of cells in the G2M phase, whereas tumor cells from starved animals were accumulated in the G0G1 phase. The fractional cell loss of tumor cell during proliferation was calculated to be around 18% higher in DFMO-treated animals compared to starved and freely fed tumor-bearing mice. This study demonstrates that different mechanisms are involved in tumor growth suppression from substrate deficiency (starvation) and from inhibition of polyamine synthesis.

Energetics of nutrition and polyamine-related tumour growth alterations in experimental cancer

“…There was no influence on water and food intake by DFMO. The tumour concentration of putrescine and spermidine decreased, while spermine concentration was unchanged by DFMO as reported elsewhere (Westin et al, 1991b). …”

“…injection of 0.1 mg g-' bw BrdUrd dissolved in 0.9% NaCl, one hour before sacrifice (Wilson et al, 1985). Tumour (Westin et al, 1991a;Westin et al, 1991b).…”

“…In line with this we recently concluded that factors interfering with the glucose homeostasis in tumour-bearing hosts can indirectly control tumour cell proliferation. This conclusion was also supported by the finding that the carbohydrate component in ordinary animal food pellets was a powerful stimulant of tumour cell proliferation by activating DNA synthesis, an effect which may be evoked by insulin (Westin et al, 1991a;Westin et al, 1991b). Changes in tumour DNA synthesis was reflected by alterations in ornithinedecarboxylase activity (ODC), which is rate limiting for polyamine synthesis (Russel, 1973;Pegg, 1988;Ota et al, 1984;Janne et al, 1978).…”

Abnormal DNA synthesis in polyamine deficient cells revealed by bromodeoxyuridine—flow cytometry technique

“…Polyamine depletion appears to have various effects on the cell cycle distribution. Some studies showed an accumulation in G, (Oredsson, Billgren & Heby 1985, Seidenfeld et al 1986, Hessels et al 1989 while others showed an accumulation in S phase (Heby, Anderson & Gray 1978, Anehus et al 1984, Oredsson et al 1990, Westin et al 1991. In some instances of ODC inhibition, prolongation of the cell cycle time was observed,without changes in cell cycle distri-bution (Seidenfeld & Marton 1980, Harada & Moms 1981.…”

Increased Urinary Polyamine Excretion in Unselected Cancer Patients Related to Host Factors

“…Increased urinary polyamine excretion has been reported in patients with solid tumours, suggesting activation of the immune system, tumour growth, increased acute-phase reaction and malnutrition in concert with elevated proliferation of various host cell populations (4)(5)(6)(7)(8). Theoretically, urinary excretion of polyamines may therefore represent a quantitative measure of tumour growth in vivo, and possibly constitutes a prognostic factor in human cancer as supported by studies in experimental cancer (9). However, other non-malignant clinical conditions such as infection, liver cirrhosis, sepsis and trauma are also associated with similar metabolic alterations including increased urinary excretion of polyamines (9 -12).…”