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Lipid metabolism in isolated hepatocytes of tumor-bearing rats
p-99
DIETARY REPLENISHMENT DECREASES THE TOXICITY OF CHEMOTHERAPY ON BONE MARROW AND INTESTINAL CRYPT CELLS OF PROTEIN DEPLETED TUMOR BEARING RATS. P.D. Dunki Jacobs, P.W. de Graaf, M.C. Ruevekamp, A.A.M. Hart, L.A. Smets, Division of experimentaT therapy, The Netherlands Cancer Institute, Amsterdam, the Netherlands. A favourable influence of adjuvant nutritional support on chemotherapy related host toxicity and tumor response remains to be established. Bone marrow and the intestinal tract are often the critical dose-limiting tissues in chemotherapy. We investigated the impact of 24-hours enteral nutritional replenishment on toxicity in Rhabdomyosarcoma bearing WAG/Rij rats. Rats were fed a protein deprived (PD) diet for 5 days,Animals were randomized to be replenished with a normal protein (NP) diet ad lib. or LO continue on PD-diet for 24-hours. Half the rats were treated with Methotrexate (MTX) i.p 30 mg/ kg body weight, the other animals were sham-injected. Tumor growth delay, percentage S-phase cells in bone marrow, intestinal crypt cell proliferation, platelets, leucocytes and MTX-plasma levels were determined. Lethality in the PD-group was 100% within 6 days after MTX treatment. Lethality in the replenished (NP) group was only 15%. Toxicity correlated with a decreased % S-phase cells determined by flow cytometry of the bone marrow in PD-rats (16.1%). Replenishment increased the % S-phase cells in the bone marrow significantly (20.2%) within 24-hours. MTX treatment decreased the % S-phase cells in the PD-group to 6.6% and in the replenished group to 13.5%. Apparently 24-hours of enteral nutritional rep?enishment with a NP-diet ad lib. was sufficient to protect against the devastating host toxicity occuring in the nutritionally depleted group. A definite statement on the tumor response related to nutritional status and replenishment is not possible because of the 100% lethality in the PD-group. Although not reaching significance a trend towards delayed MTX plasma clearance was seen and this change in the pharmacokinetics might partially explain the increased toxicity. The relationship between the nutritional status, the proliferation parameters of host's critical tissues, changed pharmacokinetics of chemotherapeutic agents, host toxicity and tumor response requires further investigation. Decreased % S-phase cells in the bone marrow of nutritionally depleted rats prior to chemotherapy seem to prognosticate host toxicity.
P.100
LIPID METABOLISM IN ISOLATED HEPATOCYTES OF TUMOR-BEARING RATS. J.M. Smit, M. Jeevanandam, M.F. Brennan (Surgical Metabolism Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA). The metabolic basis by which a malignant tumor leads to depletion of lipid stores is unknown. The liver is an appropriate organ to investigate this metabolic basis, since in tumor-bearing rats the metabolic alterations in the liver precede the changes in peripheral tissues. Using isolated hepatocytes from 24h fasted, methylcholantrene induced sarcoma-bearing, F344 male rats (TB) and equal numbers of pair-fed (NTB) controls, we measured I4C-Napalmitate (0.45;mM) oxidation to ketone bodies and I4CO2. The ketone bodies in the supernatant were also determined enzymatically. The lipogenesis was assessed using 3H2O and non-radioactive Na-palmitate (0.45 mM). We divided the TB rats into 3 groups according to the tumor burden, defined as % of body weight: group I < 5% (n=6); group II 5 to 10% (n=6); group III ) 10% (n=5). 14C02 production in tumor groups I and II and their respective control groups was comparable (mean + S.D.: 10.84 + 8.23)nmo1/106 cells/h). In group III rats palmitate oxidation to I4CO2 was-higher (211%)-than in corresponding controls (8.40 2 10.80 nmol/l06 cells/h) but the increase was not statistically significant. The rate of ketogenesis gradually Increased with increasing tumor burden and was significantly higher in group III compared to their control group or to tumor group I. The amount of ketone bodies produced by the hepatocytes is also increased with tumor burden. Preliminary results (n=6) of the lipogenesis show a small decrease (- 9%) of the lipogenesis in the TB rats compared to their pair-fed controls. Our results indicate that ketogenesis is preferentially favored over f3 -oxidation of fatty acids to CO by tumor-influenced hepatocytes and decreased lipogenesis might be responsible for tEe fat wasting often seen in cancer cachexia.
148
DIETARY REPLENISHMENT DECREASES THE TOXICITY OF CHEMOTHERAPY ON BONE MARROW AND INTESTINAL CRYPT CELLS OF PROTEIN DEPLETED TUMOR BEARING RATS. P.D. Dunki Jacobs, P.W. de Graaf, M.C. Ruevekamp, A.A.M. Hart, L.A. Smets, Division of experimentaT therapy, The Netherlands Cancer Institute, Amsterdam, the Netherlands. A favourable influence of adjuvant nutritional support on chemotherapy related host toxicity and tumor response remains to be established. Bone marrow and the intestinal tract are often the critical dose-limiting tissues in chemotherapy. We investigated the impact of 24-hours enteral nutritional replenishment on toxicity in Rhabdomyosarcoma bearing WAG/Rij rats. Rats were fed a protein deprived (PD) diet for 5 days,Animals were randomized to be replenished with a normal protein (NP) diet ad lib. or LO continue on PD-diet for 24-hours. Half the rats were treated with Methotrexate (MTX) i.p 30 mg/ kg body weight, the other animals were sham-injected. Tumor growth delay, percentage S-phase cells in bone marrow, intestinal crypt cell proliferation, platelets, leucocytes and MTX-plasma levels were determined. Lethality in the PD-group was 100% within 6 days after MTX treatment. Lethality in the replenished (NP) group was only 15%. Toxicity correlated with a decreased % S-phase cells determined by flow cytometry of the bone marrow in PD-rats (16.1%). Replenishment increased the % S-phase cells in the bone marrow significantly (20.2%) within 24-hours. MTX treatment decreased the % S-phase cells in the PD-group to 6.6% and in the replenished group to 13.5%. Apparently 24-hours of enteral nutritional rep?enishment with a NP-diet ad lib. was sufficient to protect against the devastating host toxicity occuring in the nutritionally depleted group. A definite statement on the tumor response related to nutritional status and replenishment is not possible because of the 100% lethality in the PD-group. Although not reaching significance a trend towards delayed MTX plasma clearance was seen and this change in the pharmacokinetics might partially explain the increased toxicity. The relationship between the nutritional status, the proliferation parameters of host's critical tissues, changed pharmacokinetics of chemotherapeutic agents, host toxicity and tumor response requires further investigation. Decreased % S-phase cells in the bone marrow of nutritionally depleted rats prior to chemotherapy seem to prognosticate host toxicity.
P.100
LIPID METABOLISM IN ISOLATED HEPATOCYTES OF TUMOR-BEARING RATS. J.M. Smit, M. Jeevanandam, M.F. Brennan (Surgical Metabolism Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA). The metabolic basis by which a malignant tumor leads to depletion of lipid stores is unknown. The liver is an appropriate organ to investigate this metabolic basis, since in tumor-bearing rats the metabolic alterations in the liver precede the changes in peripheral tissues. Using isolated hepatocytes from 24h fasted, methylcholantrene induced sarcoma-bearing, F344 male rats (TB) and equal numbers of pair-fed (NTB) controls, we measured I4C-Napalmitate (0.45;mM) oxidation to ketone bodies and I4CO2. The ketone bodies in the supernatant were also determined enzymatically. The lipogenesis was assessed using 3H2O and non-radioactive Na-palmitate (0.45 mM). We divided the TB rats into 3 groups according to the tumor burden, defined as % of body weight: group I < 5% (n=6); group II 5 to 10% (n=6); group III ) 10% (n=5). 14C02 production in tumor groups I and II and their respective control groups was comparable (mean + S.D.: 10.84 + 8.23)nmo1/106 cells/h). In group III rats palmitate oxidation to I4CO2 was-higher (211%)-than in corresponding controls (8.40 2 10.80 nmol/l06 cells/h) but the increase was not statistically significant. The rate of ketogenesis gradually Increased with increasing tumor burden and was significantly higher in group III compared to their control group or to tumor group I. The amount of ketone bodies produced by the hepatocytes is also increased with tumor burden. Preliminary results (n=6) of the lipogenesis show a small decrease (- 9%) of the lipogenesis in the TB rats compared to their pair-fed controls. Our results indicate that ketogenesis is preferentially favored over f3 -oxidation of fatty acids to CO by tumor-influenced hepatocytes and decreased lipogenesis might be responsible for tEe fat wasting often seen in cancer cachexia.
148