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PubMed1977

The effect of lymphoma and other neoplasms on hepatic and plasma enzymes of the host rat.

Considerable thymidine kinase and pyrroline-5-carboxylate reductase activities were found in the plasma of rats bearing a transplanted lymphoma; neither activity was detected in plasma of hosts carrying hepatic, renal, mammary, or submaxillary gland tumors. All host livers exhibited signs of biochemical immaturity as indicated by the appropriate increases or decreases in the concentrations of the nine enzymes measured. The extent and time schedule of the changes in host liver varied with the enzyme and with the tumor that caused them. The hepatic concentrations of ornithine aminotransferase, arginase, pyrroline-5-carboxylate reductase, and glucokinase (all diminished), and of peptidyl proline hydroxylase and hexokinase (increased) were sensitive indicators of tumor growth in general. The concentration of ornithine aminotransferase decreased before the tumors became palpable. At more advanced stages, the high hepatic thymidine kinase activity distinguished the presence of hepatoma and lymphoma from those of all other equally fast-growing tumors. However, only in lymphoma-bearing rats did a fivefold elevation of hepatic thymidine kinase occur as early as 4 days after implantation. Additional observations on the lymphoma itself, on blood cells, and on the involuting thymus of normal rats indicate that the striking systemic effects of this tumor cannot be explained by a release of enzymes from the thymus or by the increased number of lymphoma cells present in blood or liver.

Animals↗
PubMed1994

Growth hormone, insulin, and somatostatin therapy of cancer cachexia.

BACKGROUND: Cancer cachexia is associated with a decreased insulin:glucagon ratio. The authors hypothesized that the decrease in this anabolic hormone index is largely responsible for the progressive catabolism characteristic of cancer cachexia. Previous studies of insulin therapy alone in treating cancer cachexia have yielded limited success due to insulin-induced hypoglycemia and subsequent glucagon secretion. The current study was performed to determine the effect of combined hormone therapy (growth hormone, insulin, and somatostatin) on tumor growth, metastasis, and host metabolism. METHODS: Twenty-four female Lewis/Wistar rats (175-200 g) were subcutaneously inoculated on the flank with the MAC-33 tumor, a spontaneously metastasizing mammary adenocarcinoma. Thirty days after tumor implantation, animals were randomized to receive combined hormone therapy or saline (control) injections. Hormone therapy consisted of recombinant growth hormone (1000 U/kg/day intraperitoneally [IP]), somatostatin analogue (SMS 201-995; 150 micrograms/kg twice daily IP) and NPH humulin insulin (5 U/kg twice daily subcutaneously). RESULTS: Triple hormone therapy with growth hormone, insulin, and somatostatin significantly increased host carcass weight (211 +/- 4 g versus 179 +/- 6 g; P < 0.01) and decreased tumor:carcass ratio (0.25 +/- 0.03 versus 0.35 +/- 0.05; P < 0.01). Hamstring muscle weight and protein content were significantly increased and tumor cellular protein content was decreased in animals receiving triple hormone therapy. A significant decrease in S-phase tumor cell cycle kinetics occurred in hormone-treated versus control animals. CONCLUSIONS: Thus, combined therapy of growth hormone, insulin, and somatostatin selectively supports host anabolism and inhibits tumor growth kinetics. Combined hormone therapy specifically improves skeletal muscle protein content and reduces tumor protein incorporation. This innovative metabolic therapy for cancer cachexia may be useful in the future to prevent the progressive catabolism present in the tumor-bearing host.

Adenocarcinoma↗
PubMed1975

Subpopulations of multiparous rat lymph-node cells cytotoxic for rat tumour cells and capable of suppressing cytotoxicity in vitro.

Lymph-node cells (LNC) from multiparous pregnant rats were separated on columns prepared from nylon wool, and tested for cytotoxicity against target tumour cells. Reactivity of LNC towards hepatoma D23 and mammary carcinoma AAF57 was demonstrated in cell populations retained on the nylon wool, and not with cells eluted from the column. Although only 25% of the samples of unfractionated LNC were cytotoxic for tumour cells, retained cell fractions were cytotoxic in 11 out of 12 tests (p = less than 0.05). Similarly retained LNC were also cytotoxic for 15-day-old embryo cells but not for normal adult rat fibroblasts. Using multiparous rat serum it was shown that the reactivity of the retained LNC population could be abrogated in eight out of 11 tests (p = less than 0.05). The LNC population recovered from the nylon wool constituted 28 to 35% of the original LNC preparation, and consisted of 60-70% Ig-bearing cells together with a subpopulation of cells responding to soluble PHA. Separation of multiparous LNC on glass beads coated with rat Ig and then rabbit anti-rat Ig (in excess) also demonstrated the retained cell population to be cytotoxic against tumour cells. Approximately 17-20% of the original cell population was recovered from cells retained on the column, and consisted of an enriched Ig-bearing cell population (65-80% Ig-bearing cells) and LNC responsive to PHA. Carbonyl iron treatment of multiparous rat LNC was found to remove detectable cytotoxicity from multiparous rat LNC preparations. The cytotoxicity of multiparous rat LNC retained on nylon wool was also abolished following incubation with carbonyl iron. Definite conclusions as to the nature of the effector cell cannot be drawn from this test, since carbonyl iron treatment was found to remove not only phagocytic cells from LNC preparations but also a proportion of other cell populations including Ig-bearing lymphocytes... In addition to detecting a cytotoxic LNC population reactive towards tumour-associated embryonic antigens (retained fractions from nylon-wool column separation), a subpopulation of multiparous rat LNC was demonstrated in cell fractions eluted from the nylon wool which was shown to suppress the cytotoxicity of the retained multiparous LNC population. The exact nature of this subpopulation of LNC and the mechanism of action is at present not known.

Animals↗
PubMed1975

Cell-mediated cytotoxicity to chemically-induced rat tumours.

Cell-mediated immune reactions against carcinogen-induced rat tumours were demonstrated by the in vitro microcytotoxicity test. Lymph-node cells from syngeneic rats immunized against individual aminoazo-dye-induced hepatomas or 3-methylcholanthrene-induced sarcomas were cytotoxic for cells of the immunizing tumour compared with the effects of normal lymph-node cells. Only a low level of cross-reactivity was detectable against target cells derived from otherr tumours. Conversely, lymph-node cells from tumour -bearing rats were cross-reactive against a range of tumour cells, suggesting that the tumour-bearer was sensitized against a common antigen(s) as well as the individually specific antigen associated with these tumours. Lymph-node cells were reactive at an early time (from day 2) after tumour implantation and their cytotoxic potential persisted until terminal stages of tumour growth. Spleen cells from tumour-bearer and tumour-immune donors also exhibited comparable cytotoxic reactivities of the same specificity as that shown by lymph-node cell preparations. These findings are discussed in relation to the development of cell-mediated immune responses in the tumour-bearing rat and in immunized rats which are capable of rejecting transplanted tumour cells.

Animals↗
PubMed1994

Modulation of diethylnitrosamine carcinogenesis in rat liver and oesophagus.

A series of 16 experiments, using a total of 2,000 BD6 rats, was designed in order to assess the ability of 8 individual agents or their combinations to modulate the liver and oesophageal carcinogenesis induced by multiple doses of diethylnitrosamine (DEN). Of the antioxidants tested, sodium selenite, ascorbic acid, and butylated hydroxytoluene generally exhibited protective effects on both types of tumors. In contrast, retinoic acid behaved as a promoter of DEN hepatocarcinogenesis, but this effect could be eliminated by its combination with either selenite or butylated hydroxytoluene. Caffeine and theophylline, when individually assayed, were devoid of significant protective effects, and the latter methylxanthine stimulated oesophageal tumorigenesis when administered after exposure to the carcinogen. Caffeine tended to decrease the multiplicity of liver tumors and potentiated the inhibitory effect of selenite in the liver. Irrespective of combination with caffeine, treatment with phenobarbital before each DEN injection tended to reduce the multiplicity of both liver and oesophageal tumors. On the other hand, the metabolic inhibitor diethyldithiocarbamate, given after each DEN injection, dramatically enhanced the incidence and multiplicity of oesophageal tumors. Thus, on the whole, modulation of DEN carcinogenesis varied depending on test agents, their combinations, dosages, treatment schedules, and target organ.

Animals↗
PubMed1979

Effect of preoperative intralesional BCG and postoperative 5-FU chemotherapy in three adenocarcinoma lines in rats.

In No. 13762 mammary adenocarcinoma, it has been shown that the combination of tumor infiltration with BCG and of subsequent surgery is more curative than either treatment modality alone. And the administration of postoperative systemic 5-fluorouracil (D-FU) is equally effective in eliminating the visceral metastasis and prolonging the host survival. In the experiments reported here, two other spontaneously metastasizing adenocarcinoma lines were similarly treated. Postoperative 5-FU chemotherapy, but not intralesional BCG, significantly improved survival duration of rats with SMT-2A mammary adenocarcinoma, but neither chemotherapy nor BCG immunotherapy was effective in the new colonic adenocarcinoma line.

Adenocarcinoma↗
PubMed1993

Inhibition of tumor metastasis by a circulating suppressor factor.

Increased growth of tumor metastases has been reported after primary tumor excision in animal models. Postulated mechanisms for this phenomenon include circulating suppressor factors secreted by the primary tumor, tumor manipulation during surgical excision, and limiting nutritional factors which are consumed by both primary and metastatic tumors. To study this phenomenon, Lewis/Wistar rats with subcutaneous mammary adenocarcinoma implants (MAC-33) were randomized to receive either a standard protein diet (22.0% protein, 4.20 kcal/g) or a protein-depleted diet (0.03% protein, 4.27 kcal/g) ad lib per os. Twenty-one days after tumor inoculation, half of the animals in each dietary group underwent primary tumor excision. Control animals underwent sham excision on the flank contralateral to the tumor and physical manipulation of the primary tumor. At sacrifice 35 days after tumor inoculation, a significant increase in regional metastasis (axillary lymph nodes) and distant metastasis (lungs) occurred after primary tumor excision in animals receiving the standard protein diet. No increase in regional or distant metastases were found in animals receiving the protein-depleted diet after tumor excision. Serum was collected from animals given the standard protein diet following tumor or sham excision and added to MAC-33 tumor cell cultures for in vitro determination of tumor cell proliferation. [H3]Thymidine incorporation by MAC-33 cells in vitro was significantly suppressed by serum from tumor-bearing animals. These results imply that the biologic mechanism mediating this phenomenon is a circulating suppressor factor of tumor metastasis which is produced in tumor-bearing animals receiving standard protein (but not protein-depleted) diets.

Adenocarcinoma↗
PubMed2005

Factors controlling oxygen utilization.

We demonstrate, theoretically, that oxygen diffusion distance is related to the metabolic rate of tumors (QO2) as well as the oxygen tension. The difference in QO2 rate between tumors can vary by as much as 80-fold. Inhibition of oxygen utilization by glucose or chemical inhibitors can improve the diffusion distance. Combining respiratory inhibitors with increased availability of oxygen will further improve the oxygen diffusion distance for all tumors. A simple means for inhibiting oxygen consumption is the use of glucose (the Crabtree effect). The inhibition of tumor oxygen utilization by glucose occurs in R323OAc mammary carcinoma and 9L glioma cells. However, stimulation of oxygen consumption is observed with glucose in the Q7 hepatoma cell line. MIBG, a known inhibitor of oxygen utilization, blocks oxygen consumption in 9L, but is weakly inhibitory with the Q7. Q7 tumor cells demonstrate an anomalous behavior of glucose and MIBG on oxygen consumption. Our results clearly demonstrate the necessity for comparing effects of different agents on different tumor cells. Generalizations cannot be made with respect to the choice of inhibitor for in vivo use. Our work shows that oxygen consumption also can be inhibited with malonate and chlorosuccinate. These substrates may be effective in vivo, where glucose is low and glutamine is the major substrate. Our results indicate that information about individual tumor substrate-linked metabolic controls may be necessary before attempting to inhibit oxygen utilization in vivo for therapeutic benefit.

3-Iodobenzylguanidine↗
PubMed1995

Nutrients, signal transduction and carcinogenesis.

Choline phospholipids play major roles in cellular regulation in addition to their essential function as structural components of membranes and lipoproteins. The unique functions of choline phospholipids as hormones (platelet activating factor, 1-alkyl, 2-acetylphosphatidylcholine, PAF) and sources (phosphatidylcholine, sphingolipids) of second messengers (sphingosine, diacylglycerol, lysophospholipids, arachidonic acid and its metabolites) may explain how dietary choline influences normal physiological processes as well as a diverse group of pathological processes, including carcinogenesis.

Animals↗
PubMed1997

Evaluation of the concept of "hypoxic fraction" as a descriptor of tumor oxygenation status.

The presence and significance of tumor hypoxia has been recognized since the 1950's. Hypoxic cells in vitro and in animal tumors in vivo are documented to be three times more resistant to radiation-induced killing compared to aerobic cells. There is now evidence that tumor hypoxia is treatment-limiting in many human cancers. One common way to describe the extent of hypoxia in individual and groups of tumors is the "hypoxic fraction." This measurement infers that cells are present in only two radiobiologically significant states: oxygenated and hypoxic. In this paper, we demonstrate the qualitative and quantitative presence of hypoxic tumor cells using the oxygen dependent metabolism of the 2-nitroimidazole, EF5. Two assumptions concerning the calculation and interpretation of the hypoxic fraction are considered. The first is the use of multiple animals to describe the radiation response at a given radiation dose. We hypothesize that the presence of intertumor variability in radiation response due to hypoxia could negatively influenced the characterization of the change in slope required to calculate the hypoxic fraction. The studies presented herein demonstrate heterogeneity of radioresponse due to hypoxic fraction within and between tumor lines. The 9L subcutaneous tumor studied in air-breathing rats demonstrates a 2 log variation in surviving fraction at 17 Gy. The Morris 7777 hepatoma, in contrast, showed little variability of radiation response. Our second question addresses the limitations of using the "hypoxic fraction" to describe the radiation response of a tumor. This calculated value infers that radiobiological hypoxia is a binary measurement: that a tumor contains two cell populations, aerobic cells with maximal radiosensitivity and hypoxic cells with maximal radioresistance. The classic work of Thomlinson and Gray, however, implies the presence of an oxygen gradient from tumors vessel through the tissues. In both the 9L and Q7 tumors, flow cytometric analysis of EF5 binding demonstrates a continuous range of cellular pO2 levels. These studies suggest that: 1) there is extensive intertumor variability of radiation response in certain tumor lines; 2) the variability in radiation response between individual tumors in a group may affect the ability to describe a particular tumor type's "hypoxic fraction" and 3) The oxygen status of tumor cells is a continuum. This realization affects the ability to apply a binary concept such as the "hypoxic fraction" effectively in radiobiology.

Animals↗