Aerobic exercise as therapy for cancer fatigue.

PURPOSE: Fatigue and impairment of physical performance are common and severe problems of cancer patients. We describe the effect of an aerobic exercise program designed for cancer patients suffering from these symptoms. METHODS: Five cancer patients (4 female, 1 male, age 18 to 55), participated in the training program. Fatigue had been present for a time ranging between 5 wk and 18 months and hindered the patients from carrying out normal daily activities. The training program consisted of walking daily on a treadmill with an intensity corresponding to a lactate concentration of 3 +/- 0.5 mmol.L-1 and was carried out for 6 wk. RESULTS: By the end of the exercise program we observed an improvement in maximal physical performance (from 6.4 +/- 0.4 km.h-1 to 7.5 +/- 0.9 km.h-1, P < 0.05) and maximal walked distance (from 1640 +/- 724 m to 3300 +/- 953 m, P < 0.05). Heart rate and lactate concentration by an equivalent submaximal workload (5 km.h-1) were significant reduced (from 138 +/- 21 beats.min-1 to 113 +/- 20 beats.min-1, P < 0.05, and from 2.6 +/- 1.4 mmol.L-1 to 1.3 +/- 0.6 mmol.L-1, P < 0.05); all patients experienced a clear reduction of fatigue and could carry out normal daily activities again without substantial limitations. CONCLUSION: We conclude that an aerobic exercise program of precisely defined intensity, duration, and frequency can be prescribed as therapy for primary fatigue in cancer patients.

Rapid decline in folylpolyglutamate synthetase activity and gene expression during maturation of HL-60 cells. Nature of the effect, impact on folate compound polyglutamate pools, and evidence for programmed down-regulation during maturation.

These studies in HL-60 cells examined the regulation of folylpolyglutamate synthetase (FPGS) activity at the level of gene expression during terminal maturation. Following addition of 210 mM Me2SO to cultures of HL-60 cells at a concentration that induces maturation of 85-90% of the cells, FPGS activity, but not folylpolyglutamate hydrolase (FPGH) activity, was reduced 2-7-fold within 1-5 days. The initial decline in FPGS activity preceded any effect of Me2SO on rate of growth and the increase in appearance of nitro blue tetrazolium-positive cells, a marker of cellular maturation, and the decrease after 5 days of exposure to Me2SO was solely accounted for by a 7-fold decrease in value for Vmax. The same time and concentration dependence for Me2SO was shown for the decline in FPGS activity, increase in nitro blue tetrazolium-positive cells, and decline in the level of a 2.1-kilobase FPGS mRNA during exposure to this inducer. This decline in FPGS mRNA was reversible when Me2SO was removed from the culture medium but only until that time when an appreciable number of cells were committed to terminal maturation. Following growth of HL-60 cells with [3H]MTX, used as a model folate compound, a large reduction in its intracellular polyglutamate pools was shown during maturation which quantitatively reflected the decline in FPGS activity as well as folate transport inward (Sirotnak, F.M., Jacobson, D.M., and Yang, C-H. (1986) J. Biol. Chem. 261, 11150-11156). Other data showed that folate status or obviation of the folate requirement during growth of these cells strongly influenced the rapidity of the onset of maturation following exposure to inducer. Overall, these results show that FPGS activity in HL-60 cells is a marker for proliferative capacity and that the underlying basis for the decline in FPGS activity during maturation is altered cognate gene expression which is manifested as early reversible and late irreversible phases. They also suggest that the coordinate reduction observed in folate transport, FPGS activity, dihydrofolate reductase, and probably other folate related enzymes by limiting macromolecular biosynthesis may be early programmed events in the maturation process that influence the switch from proliferation to senescence in these cells.

Differing specificities for 4-aminofolate analogues of folylpolyglutamyl synthetase from tumors and proliferative intestinal epithelium of the mouse with significance for selective antitumor action.

Folylpolyglutamyl synthetase (FPGS), partially purified from murine L1210 leukemia and Sarcoma 180 cells and the proliferative fraction of luminal epithelium from mouse small intestine (the site of limiting toxicity to folate analogues), was examined for its ability to utilize various 4-aminofolates as substrates. For tumor-derived FPGS, aminopterin was the most preferred substrate overall, exhibiting the lowest value for apparent Km and highest Vmax. The other analogues and folic acid exhibited nearly 2-fold lower Vmax. Folic acid exhibited a 3-fold higher Km than aminopterin. Alkylation of aminopterin (methotrexate) or carbon for nitrogen substitution (10-deazaaminopterin) at N-10 increased Km 3- to 6-fold, while alkylation at C10 (10-ethyl-10-deazaaminopterin) restored Km to near equivalency with aminopterin. For FPGS derived from proliferative intestinal epithelium, aminopterin was also the preferred substrate, but the value for Vmax (derived with crude cell-free extract) was 6-fold lower than for tumor cell FPGS. Values for Vmax (derived with partially purified FPGS) for the other 4-aminofolate analogues and folic acid were similar (methotrexate) or 2-fold (10-ethyl-10-deazaaminopterin) and 5-fold (folic acid) lower than for aminopterin. The value for Km derived with aminopterin was similar to that derived for either tumor cell FPGS. The value for folic acid was 2-fold higher, and alkylation of aminopterin (methotrexate) or carbon to nitrogen substitution (10-deazaaminopterin) at N-10 with (10-ethyl-10-deazaaminopterin) or without alkylation markedly increased Km (27-, 90-, and greater than 100-fold, respectively, for methotrexate, 10-ethyl-10-deazaaminopterin, and 10-deazaaminopterin). In other studies, it was found that the diglutamate of aminopterin (aminopterin +G1) was a relatively poor substrate for FPGS derived from all three sources compared with methotrexate diglutamate, both in respect to values for Km and Vmax that were measured in each case. Findings with FPGS derived from L1210 cells were confirmed by high-pressure liquid chromatography analysis of product formation during the reaction with the parent compounds. The significance of the results presented here to the question of relative toxicity and therapeutic activity of these analogues is discussed.

Preferential selection during therapy in vivo by edatrexate compared to methotrexate of resistant L1210 cell variants with decreased folylpolyglutamate synthetase activity.

Acquired resistance of the L1210 leukemia in mice developed with less rapidity during therapy with edatrexate (10-ethyl-10-deazaaminopterin, EDX) than with MTX. Since this was explained only partially by the somewhat greater antitumor activity of EDX, this result may also reflect a difference in biochemical phenotypes selected in each case. Among 20 sublines selected for resistance to MTX, a reduction in influx, an elevation of DHFR, and a reduction of DHFR inhibition by MTX were all delineated. Among 14 sublines selected for resistance to EDX, both a reduction in influx and an elevation in level of DHFR were also commonly found. In addition, however, 7 of 14 EDX-resistant sublines exhibited a reduction in the level of folylpolyglutamate synthetase (FPGS) activity. Clonal derivatives of these 7 EDX-resistant cell lines exhibited 2- to 28-fold reductions in FPGS activity and a commensurate reduction in [3H]-MTX polyglutamate formation in situ following exposure to [3H]-MTX during growth in mice. An analysis of the kinetics and relative substrate preferences for FPGS from variant and parental L1210 cells revealed that the various changes in FPGS activity were at the level of the Vmax rather than Km. These results derived from an in vivo tumor model provide further evidence for a role of FPGS as a determinant of cytotoxicity and acquired resistance to classical folate analogs. They also provide evidence in the same pharmacologic model for a manifestation of resistance to 4-aminofolates in vivo that involves all of the alterations of its primary target, transport, and metabolism that have ever been associated with acquired resistance in cell culture systems.