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[CANCER RESEARCH 31, 1955-1961, December 1971] Effect of Mammary Tumor Virus Infection on in Vivo Oxidation of Glucose-l-14C and Glucose-6-14C in C3H Mice1 Hans R. Burki2 and George T. Okita Northwestern University Medical School, Department of Pharmacology, Chicago, Illinois 60611 SUMMARY The in vivo oxidation of glucose-1-14C and glucose-6-14C was measured in C3H and C3Hf female virgin mice of different ages. C3H virgins after the age of 4 to 6 months exhibited a faster rate of glucose-6-14C, but not glucose-1-14C, oxidation than C3Hf factor-free controls. No difference was observed between the two strains of mice with respect to the blood glucose level, but C3H virgins attained lower body weights than C3Hf controls. These results suggested that the mammary tumor virus, transmitted in the milk of C3H mice, may induce in the host alterations in regulatory systems controlling growth and glucose metabolism. The presence of a transplanted mammary tumor, which had arisen spontaneously in a C3H exbreeder female, had no effect on body weight and glucose-6-'4C oxidation of C3H virgins but caused an elevation in glucose-6-14C oxidation and a reduction in body weight in C3Hf virgin hosts. Thus, the level of glucose-6-14 C oxidation and the body weight of C3Hf recipients of mammary tumor transplants were comparable to that of C3H virgins with or without mammary tumor transplants. controls. There also appeared to exist a correlation between the magnitude of the metabolic changes and the extent of cancerous involvement of the mammary tissue in these mice. For example, C3H exbreeders with multiple tumors showed the greatest deviations in in vivo glucose metabolism. These observations seemed to suggest that the increased mammary tumor yield observed in MTV-infected animals may be related to distortions of physiological metabolic control systems in the host by MTV (10). Thus, further experiments were carried out to explore the consequences of MTV infection on glucose metabolism in vivo. The purpose of the present study was 2-fold: (a) to investigate the temporal development of alterations in glucose metabolism in vivo in C3H virgins. Thus, the rate of oxidation of glucose-l-I4C and glucose-6-14C was compared in C3H and C3Hf virgins of different ages; (6) to determine whether the presence of small foci of tumor tissue might elicit a host response, hormonal or immunological, which may lead to alterations in glucose metabolism in vivo. For this purpose, the degradation of glucose-14C was measured in mice with transplanted mammary tumors. MATERIALS AND METHODS INTRODUCTION Early studies on the genesis of mammary tumors in C3H mice led to the concept that 3 factors are essential for the development of mammary tumors: milk-transmitted MTV,3 Mice. C3H and C3Hf female mice were obtained from The Jackson Memorial Laboratory, Bar Harbor, Maine, and from Cumberland View Farm, Clinton, Tenn. In one experiment, C3H and C3HfB females, generously donated to us by Dr. Walter Heston, NIH, were used. The animals were kept in our animal quarters for at least 1 month before use and had access to water and standard mouse diet of Purina laboratory chow pellets ad libitum. Chemicals. D-Glucose-1 -14C(specific activity, 7 mCi/mmole) inherited mammary tumor susceptibility, and hormonal stimulation of the breast tissue (6). More recent studies, however, indicated that the MTV may not be necessary for tumorigenesis (8, 11, 12) and that adequate hormonal stimulation of the mammary glands, in genetically susceptible mice, may be sufficient for mammary carcinogenesis. Recently, papers of Batra and Okita (5), Ezz et al. (10), and Okita et al. (18, 19) described alterations in in vivo oxidation of specifically labeled glucose-14 C to I4C02 in MTV-infected C3H mice compared to factor-free C3Hf controls. Precancerous and tumor-bearing C3H females exhibited a faster rate of glucose-6-14C oxidation and also a lower ratio of glucose-l-14C to glucose-6-14C degradation than did C3Hf were diluted with 0.9% NaCl solution under sterile conditions (Millipore filtration) to a concentration of about 4/jCi/ml. These sterile solutions were stored in the deep freeze at -10°. At regular intervals, the glucose-l-14C and glucose-6-'4C 'This investigation was supported by USPHS Research Grant CA 07930 from the National Cancer Institute and NIH Training Grant GM-00162 from the National Institute of General Medical Sciences. 2Present address: Research Institute, Dr. A. Wander Ltd., P. O. Box 2747, 3001 Bern, Switzerland. 3The abbreviation used is: MTV, mammary tumor virus. Received January 26, 1971; accepted August 3, 1971. solutions were checked for purity by paper chromatography (10). Blood Glucose. Blood glucose levels were determined with a Technicon Auto Analyzer by a procedure utilizing the potassium ferricyanide-potassium ferrocyanide oxidation reduction reaction as described by Hoffman (13). The change in color was measured at 420 mß. was obtained from Nuclear Research Chemicals, Inc.. Orlando, Fla. D-Glucose-6-14C (specific activity, 27.5 mCi/mmole) was obtained from Nuclear Chicago, Chicago, 111. For injection purposes, glucose-1-14C and glucose-6-14C DECEMBER Downloaded from cancerres.aacrjournals.org on August 2, 2017. © 1971 American Association for Cancer Research. 1955 Hans R. Burki Estimation of Tumor Size. The tumor volumes were estimated by the formula V= (0.4) ab2, where a equals longest RESULTS axis of tumor in millimeters, b equals shortest axis in millimeters, and V equals volume in cu mm (1). Tumor volumes calculated with this formula were in close agreement with those found by immersing the tumors in 0.9% NaCl solution. Measurement of Expired C02 and 14CO2. The apparatus Recovery Patterns of CO2 and 14C02. Chart 1 shows a sample of C02 and 14C02 recovery patterns from a mouse given an injection of glucose-6-14C, 0.02 ¿/Ci/gi.p. (injection used has been described previously (16) and consisted of the following components: an all-glass mouse chamber and a freezing trap (C02-acetone mixture) connected in series with a 250-ml ionization chamber (Gary stainless steel spherical ionization chamber) and a CO2 analyzer (Lira Model 300 infrared analyzer). Outputs from both the ionization chamber and the C02 analyzer were recorded on a Speedomax recording instrument (Speedomax G Model S Multiple Point Recorder) as well as fed into an analog-to-digital converter. The digital output was recorded on a paper tape punch (Friden tape punch). The equipment was standardized with gases containing 0.5 and 1.0% CO2 in air as well as with a gas containing a known amount of 14C02 in air. The experiments were performed in air-conditioned laboratories where the room temperature varied between 22 and 24°. Mice deprived of food for 8 to 14 hr were given i.p. injections of 0.02 i/Ci/g glucose-14 C and placed into the mouse chamber. A continuous flow of air of 250 ml/min was established through the entire system, and a recording of the expired CO2 and 14C02 was taken every 20 sec. In most instances, it was sufficient to measure the recovery of 14C02 at O min). For simplification of the presentation of data in this chart, the amounts of CO2 and 14C02 excreted were pooled into 5-min segments. Chart 1 demonstrates that the C02 excretion was high for the first several min after the animal was treated and placed into the mouse chamber. This initial peak output of C02 correlated with the exploratory activity of the animal. Later the rate of the CO2 excretion dropped off considerably as the animal went to sleep. Occasional physical activity resulted in increased output of CO2. The recovery of 14CO2 increased rapidly within 25 to 30 min after the injection of glucose-6-14C to reach a peak after 30 to 40 min. At times of elevated C02 excretion, the recovery of 14C02 was also increased. However, as expected, the specific activity curve was not appreciably affected by the physical activity of the animal. The specific activity curve rose to a maximum between 25 and 40 min after the injection of glucose-6-14C and decreased steadily thereafter. The cumulative specific activity curve, 15 to 20 min after the injection of glucose-6-14C, entered a near-linear phase. The slope of this 05- for 40 min. In some experiments, the measurements were extended to 60 min. The length of the recording is indicated in the respective tables. All calculations were performed on an IBM 1800 digital computer utilizing the data punched on to the paper tape. For each 20-sec segment, the recovery of 14C02 was determined (expressed in percentage of the injected dose of glucose-14C), and the excretion of C02 was measured (mmoles CO2 corrected to 0°and 760 mm Hg). Adding all 180 (= 60 min) or 120 (=40 min) 20-sec segments yielded the cumulative recovery of 14CO2 and the total excretion of C02 for 60 and 40 min, respectively. Also, for each 20-sec segment, the specific activity (percentage of injected glucose-14C excreted as 14C02 per mmole of CO2) was calculated. The slope of the cumulative specific activity curve of 14C02 was calculated, with the use of all data points between 20 and 40 min after injection of glucose-14C, by the method of least squares. This slope (expressed as percentage of 14C excreted as 14CO2 per mmole of C02 per hr) represents the average specific activity of the expired ' 4CO2 and is used in this paper to compare the metabolic activities of different treatment groups. As in previous studies (10, 19), glucose-1-14C glucose-6-14C were selected as substrates for and the measurements of in vivo oxidation of glucose. These compounds are often used to evaluate the relative participation of the Embden-Meyerhof pathway and the pentose cycle in the degradation of glucose (15). Statistics. Statistical significance was determined by the Student t test. 1956 20 60 80 100 TIME, MINUTES KO 160 Chart 1. CO2 and I4CO2 excreted by a C3H mouse, age 40 weeks, givenan i.p. injection, at O min, of glucose-6-14C, 0.02 /iCi/g. CANCER RESEARCH VOL. 31 Downloaded from cancerres.aacrjournals.org on August 2, 2017. © 1971 American Association for Cancer Research. Glucose Metabolism in C3H Mice GLUCOSE-I-UC linear portion proved to be highly reproducible in animals of the same treatment group and independent of their physical activity. Therefore, this slope (14C02 in percentage of injected glucose-14C per mmole of CO2 per hr) was considered not only an accurate but also a convenient measurement of the rate of glucose-14 C degradation and is used in this paper to compare the metabolic activity of different treatment groups. In Vivo Oxidation of Glucose-14C in C3H and C3Hf Virgins of Different Ages. The first objective of this study was to investigate the temporal development of the metabolic differences between C3H and C3Hf mice observed by Okita and coworkers. For this purpose, the rate of oxidation of glucose-1-14C and glucose-6-14C to 14C02 in vivo was measured in C3H and C3Hf virgins of different ages. All animals used for this study were free of mammary tumors. The results of these experiments are presented in Chart 2 and in Tables 1 and 2. Chart 2 shows the specific activity curves and the cumulative specific activity curves of expired 14C02 of 60-week-old C3H and C3Hf virgins, given i.p. injections of glucose-l-'4C or glucose-6-14C, 0.02 ¿iCi/g. It may be GLUCOSE -6- '*C 15- observed that there was no difference in the rate of excretion of 14CO2 in terms of specific activity when glucose-l-14C was used as substrate. In contrast, the rate of conversion of glucose-6-14C to 14C02 was increased in C3H virgins 40 O 10 TIME. MINUTES Chart 2. Specific activity curves and cumulative specific activity curves of expired "CO2 of C3H (o) and C3Hf (•)virgins, 60 weeks old, given i.p. injections of glucose-1-1 *C or glucose-6-' 4C. Each point is the average of 5 to 6 mice. compared to C3Hf controls, the slope of the cumulative specific activity curve for C3H virgins being significantly greater (p < 0.01) than that of C3Hf controls. Table 1 presents a summary of the results of measurements of glucose-6-14C oxidation in C3H and C3Hf virgins of different ages. At the age of 18 weeks, no differences were apparent between the 2 strains of mice with respect to body Table 1 In vivo oxidation of glucose-6-'4C in C3H and C3Hf mice of different ages Mice were given i.p. injections of glucose-6-"C, 0.02 jiCi/g, and the expired '4CO2 was measured as described in "Materials and Methods." All values are mean ±S.E. "C recovered min(%)36.68 0—60 C02 0—60min (mmoles)2.70 of cumulative specific activity curve (% "CO2/mmole CO./hr)19.60 miceAge State of (g)19.0 wkC3Hf 18 virginsC3H virginsAge 0.320.2 ± 0.6n.s."28.7 ± 2.4630.82 ± 1.50n.s.24.66 ± 0.282.31 ± 0.14n.s.2.82 ± 0.3320.52 ± 1.41n.s.14.25 ± ±1.123.6 ±0.7p 0.0125.8 < 0.9426.80 ± 3.06n.s.21.83 ± 0.132.37 ± 0.21n.s.2.70 ± 0.7017.22 ± 0.84p± 0.0513.72 < 1.0825.64 ± 0.082.56 ± 0.08n.s.3.27 ± 0.5416.64 ± 0.83p± 0.0211.60 < wk"C3Hf 40 virginsC3H virginsAge wk*C3Hf 46 virginsC3H virginsAge 0.523.4 ± 0.5p ± 0.0130.3 < 2.85n.s.25.51 ± wkC3Hf 60 virginsC3H 0.825.9 ± 2.1429.77 ± 0.223.05 ± virginsNo.55656556Weight 0.7p ± 2.65n.s.Total ± 0.21n.s.Slope ± < 0.02Total 0.2515.02 ± 0.89p ± < 0.01 'n.s., not significant. 1Duration of experiments. 40 min. DECEMBER 1971 Downloaded from cancerres.aacrjournals.org on August 2, 2017. © 1971 American Association for Cancer Research. 1957 Hans R. Burki Table 2 In vivo oxidation of glucose-1-"C in C3H and C3Hf mice of different ages Mice were given i.p. injections of glucose-l-"C, 0.02 ¿iCi/g,and the expired "CO2 was measured as described in "Materials and Methods." All values are mean ±S.E. "Crecovered0—60 min(%)45.03 cumulativespecific of curve(% activity "CO2/mmoleC02/hr)19.15 min(mmoles)3.29 —60 4.1336.02 3= 3.25n.s.34.20 ± 0.232.78 ± 0.28n.s.3.37 ± miceAge State of wkC3Hf 18 virginsC3H virginsAge ±1.1419.4 0.94n.s."30.2 ± wkC3Hf 60 virginsC3H ±1.1126.6 2.1233.25 ± 0.133.02 ± virginsNo.6555Weight(g)20.0 1.07p± 2.47n.s.TotalCO20 ± 0.07n.s.Slope ± < 0.05Total 0.4719.92 ± 1.39n.s.15.67 ± 0.7815.96 ± 0.99n.s. ± " n.s. not significant. Table 3 In vivo oxidation of glucose-6-"C in C3H and C3HfB mice" of different ages Mice were given i.p. injections of glucose-6-"C, 0.02 nC\/g, and the expired "CO2 was measured as described in "Materials and Methods." All values are mean ±S.E. "Crecovered0—40 min(%)18.48 cumulativespecific of curve(% activity min(mmoles)1..82 "CO2/mmoleC02/hr)17.73 0.7226.36 ± 3.44p± 0.0520.52 < 0.042.15 ± 0.08p ± 0.012.51 < miceAge State of wkC3HfB 15 virginsC3H virginsAge 0.720.0 ± 1.7p ± 0.0529.00 < wkC3HfB 19 virginsC3H 0.919.25 ± 2.0531.47 ± 0.092.10 ± virginsNo.6464Weight(g)24.5 0.6p ± 3.18p± 0.05p ± < 0.01Total < 0.02TotalCOZ0—40 < 0.01Slope 1.3419.66 ± 1.56n.s.613.44 ± 0.2320.11 ± 0.83p ± < 0.01 "C3H and C3HfB females obtained from Dr. W. Heston, NIH. a n.s., not significant. weight and glucose-6-'4C oxidation as measured by the slope of the cumulative specific activity curve. Part of the variations in total recovery of 14CO2 and in the total amount of C02 excreted is due to differences in random physical activity. At 40, 46, and 60 weeks, however, C3H mice oxidized glucose-6-14C significantly faster and had lower body weights than did C3Hf controls. In Table 2 are summarized the results of measurements of glucose-1-1 4C degradation in 18- and 60-week-old C3H and C3Hf virgins. There was again a significant difference in body weight between the 2 strains at 60 weeks but not at 18 weeks. Contrary to the findings with glucose-6-14C, no significant differences were found at either age between C3H and C3Hf mice with respect to the rate of glucose-1-14C oxidation. Thus, the ratio glucose-l-"*C/glucose-6-14 C degradation was 0.98 for C3Hf and 0.97 for C3H mice, respectively at 18 weeks. At 60 weeks, these ratios were 1.35 forC3Hfand 1.06 for C3H virgins, respectively. The measurements of glucose-6-14C degradation and body weight were repeated with C3H and C3HfB virgin females from Dr. Heston's laboratory. As indicated in Table 3, significant differences between the 2 strains of mice with respect to body weight were already apparent at 15 weeks of 1958 Table 4 Blood glucose levels in blood collected from the tails of C3H and C3Hf mice, ages 64 to 66 weeks glucose (mg/100 ml)104.3 GroupsC3Hf virgins C3H virginsNo.11 9Blood ±4.9« 97 . 1 ±2.5 " Mean -HS.E. age, while a significant difference in glucose-6-'4C oxidation between C3H and C3HfB virgins was observed at 19 weeks of age. Since it is known that the rate of the in vivo oxidation of glucose-14 C is in part dependent on the body glucose pool, the blood glucose level was measured in 64- to 66-week-old C3H and C3Hf virgins. Table 4 shows that there was no significant differences between these 2 strains with respect to the blood glucose level. In Vivo Oxidation of Glucose-14 C in C3H and C3Hf Virgins with Transplanted Mammary Tumors. Because C3H mice of age 5 to 6 months and older (14) develop precancerous hyperplastic nodules in the mammary tissue which are CANCER RESEARCH VOL. 31 Downloaded from cancerres.aacrjournals.org on August 2, 2017. © 1971 American Association for Cancer Research. Glucose Metabolism in C3H Mice BODY ü C3Hf VIRGINS D VIRGINS C3H TUMOR WEIGHT VOLUME T T 4 I 32 s28 D 1200- g 24 ÃœJ >1000- QC O 800- O 16 z o m 12 Oi Chart 3. Body weights and mammary tumor volumes of C3H and C3Hf virgins. T, recipients of tumor transplants. UJ P 600^ _ 400- 8 E 2003 0 DAYS 35 AFTER 8 TUMOR In vivo oxidation 35 TRANSPLANTATION of glucose-6-"C Table 5 in C3H and C3Hf virgins, age 40 weeks, with transplanted mammary tumors Mice were given i.p. injections of glucose-6-"C, 0.02 ¿iCi/g,and the expired "CO2 was measured as described in "Materials and Methods." Values are mean ±S.E. Weight1.2.3.4.GroupsC3Hf Tumor volume mm)28.131 cumulative specific(g)76*i1.0.16< activity curve ColminoleC02/hr).2524<22<40<it0.±0.•i0.0.701.320 virginsC3Hf tumortransplant"C3H virgins with 22P23P849 ±63 0.01".6<.2<±0t00.010.,0l7A61418.P17.P18.Pof virginsC3H tumortransplant"No.6656(cu virgins with 23p ±214 < 0.05' pSlope °35 days after tumor transplantation. "Compared to Group 1. 'Compared to Group 2. characterized by a high tumorigenic potential (17), size in both strains of mice. These tumor nodules increased experiments were therefore designed to test the possibility progressively in size in C3H virgins only, however, while their that the alterations in glucose-6-I4C oxidation and in body growth in C3Hf virgins appeared to be retarded. Table 5 presents a summary of the results of measurements weight observed in C3H females compared to factor-free of in vivo oxidation of glucose-6-14C in C3H and C3Hf virgins controls could be related to the presence of small foci of tumor tissue in the mammary gland, eliciting a host response with transplanted mammary tumors, 35 days after the of hormonal or immunological nature (7). For this purpose, 1 inoculation. In C3H virgins, neither the body weight nor the rate of glucose-6-14C degradation was altered in the presence mammary tumor, surgically removed from a C3H exbreeder where it had arisen spontaneously, was homogenized in 0.9% of the tumor transplant. In C3Hf virgins, on the other hand, the transplantation of the mammary tumor resulted in a NaCl solution ( l g tumor tissue per 10 ml 0.9% NaCl solution), and 0.1 ml of this homogenate was injected s.c. into each of 6 significant reduction in body weight and a significant increase in glucose-6-14C oxidation compared to C3Hf controls. With C3Hf and 6 C3H virgins. Six C3Hf and 5 C3H virgin mice of respect to body weight and glucose-6-14C oxidation, the C3Hf the same age (35 weeks) were used as untreated controls. Body weights and glucose-6-14C oxidation were measured 35 days virgins with transplanted tumor tissue exhibited now the characteristics of C3H mice. after transplantation of tumor tissue (Chart 3, Table 5). Chart 3 indicates that the transplantation of the mammary tumor caused a significant reduction (p<0.01) in body DISCUSSION weight in C3Hf but not C3H virgins. It may also be observed The yields of expired 14C02 from glucose-1-C and that until around 8 days after inoculation, the tumor nodules glucose-6-14C may be used, after making several simplifying arising from the sites of transplantation were about equal in DECEMBER 1971 Downloaded from cancerres.aacrjournals.org on August 2, 2017. © 1971 American Association for Cancer Research. 1959 Hans R. Burki assumptions, to estimate the relative participation of the pentose cycle and the glycolysis-Krebs cycle pathway in the metabolism of glucose (15). In this study, it was found that, after the mice were about 4 months old, the rate of oxidation of glucose-6-14C, but not of glucose-1-14C, was increased in MTV-infected C3H mice when compared to factor-free controls of the same age. This suggests that there was no difference between the 2 strains of mice with respect to metabolism via the pentose cycle, whereas there was an increased degradation via the glycolysis-Krebs cycle pathway in C3H mice compared to controls. Similar findings have been published previously (5, 10, 18, 19). Since it was also noted that MTV-infected C3H mice attained lower body weights than did C3Hf controls, it seems likely that the alterations in glucose-6-14C oxidation in C3H mice when compared to be to create in the host conditions favorable for tumor growth, provided that the MTV is introduced into the animal at an early age (14). Thus it has been shown, with recipients of transplants of mammary tissue from different strains of mice, that the susceptibility of tumor development is determined at the level of the mammary gland tissue (8, 9). The presence of MTV in the recipients of mammary tissue transplants resulted in a reduction of the average tumor detection age from 400 to 600 days to 200 to 300 days (8). Thus, one may speculate that the reduction of the average tumor detection age in MTV-infected mice may have been related to metabolic alterations produced in the host by the presence of MTV. controls were caused by a general alteration in regulatory systems controlling growth and glucose metabolism. With the available data, no statement can be made about the nature of the regulatory systems presumed to be affected, although there is evidence that in vivo glucose-14C metabolism in C3H 1. Attia, M., and Weiss, D. Immunology of Spontaneous Mammary Carcinomas in Mice. V. Acquired Tumor Resistance and Enhancement in Strain A Mice Infected with Mammary Tumor Virus. Cancer Res., 26: 1787-1800, 1966. 2. Barrett, M. K., and Deringer, M. K. The Effect of Foster Nursing on the Growth of a Transplantable Tumor. Cancer Res., ¡I: 134-138, 1951. 3. Barrett, M. K., Deringer, M. K., and Dunn, T. B. Influence of the Mammary Tumor Agent on the Longevity of Hosts Bearing a Transplanted Tumor. J. Nati. Cancer Inst., 13: 109-119, 1952. 4. Barrett, M. K., and Morgan, W. C. A Maternal Influence on the Growth Rate of a Transplantable Tumor in Hybrid Mice. J. Nati. Cancer Inst., JO: 81-88, 1949. 5. Batra, K. V., and Okita, G. T. Effect of Spontaneous Mammary Carcinogenesis on in Vivo Glucose-U-' *C Incorporation in C3H Mice. Proc. Soc. Exptl. Biol. Med., 125: 1163-1168, 1967. 6. Bittner, J. J. Genetic Concepts in Mammary Cancer in Mice. Ann. N. Y. Acad. Sci., 71: 943-975, 1957- 1958. 7. Dezfulian, M., Zee, T., DeOme, K. B., Blair, P. B., and Weiss, D. W. Role of the Mammary Tumor Virus in the Immunogenicity of Spontaneous Mammary Carcinomas of BALB/c Mice and in the Responsiveness of the Hosts. Cancer Res., 28: 1759-1772, 1968. 8. Dux, A., and Muhlbock, O. Susceptibility of Mammary Tissues of Different Strains of Mice to Tumor Development. J. Nati. Cancer Inst., 40: 1259-1265, 1968. 9. Dux, A., and Muhlbock, O. Propagation of the Mammary Tumor Agent (Bittner Virus) in the Absence of Mammary Glands in Mice. J. Nati. Cancer Inst., 40: 1309-1312, 1968. mice can be influenced by altering the hormonal status of the animals (10, 19). The age at which differences in glucose metabolism and growth between C3H and C3Hf mice became apparent varied according to the source of the mice. Enhanced oxidation of glucose-6-14C and reduction in growth occurred earlier in C3H mice when these mice were compared with the C3HfB strain than when compared with C3Hf mice. It seems reasonable to assume that the differences in metabolic characteristics between the 2 C3Hf strains may have been caused by prolonged inbreeding in different institutions with consequent selection for slightly different genetic traits. Attempts were made to elucidate possible factors that may have caused the differences in growth and glucose metabolism between C3H and C3Hf mice. Since only virgin mice were used, metabolic alterations resulting from pregnancy and lactation can be excluded. The age (4 to 6 months) at which metabolic differences between C3H and C3Hf females became detectable coincides with the age at which hyperplastic alveolar nodules develop in the mammary tissue of C3H females (14). Thus, it appeared likely that alterations in glucose-14C metabolism and growth in C3H females when compared to factor-free controls may have been due to a host response to the presence of the tumor tissue. However, in this study it was shown that the presence of a transplanted mammary tumor had no effect on body weight and glucose-6-14C oxidation of C3H mice. It was therefore concluded that the presence of a tumor mass per se had no effect ontheseparameters. C3Hf recipients of mammary tumor transplants, on the other hand, showed an elevated rate of glucose-6-14C oxidation and a reduction in body weight. This appeared to suggest that the transplantation of mammary tumor tissue resulted in infection of the C3Hf recipients with MTV and probably other pathogens, thus causing a reduction in body weight and an alteration in glucose-6-14 C oxidation. In the present experiments, it was also found that mammary tumor transplants grew well in C3H recipients but not in C3Hf mice, a finding that has also been reported by others (2—4,7). This seemed to suggest that one important role of MTV may 1960 REFERENCES 10. Ezz, E. A., Okita, G. T., and LeRoy, G. V. Spontaneous Carcinogenesis in C3H Mice. In: The Use of Radioisotopes in Animal Biology and the Medical Sciences, pp. 217-234. New York: Academic Press, Inc., 1961. 11. Hagen, E. O. The Induction of Mammary Tumors in Male Mice by Pituitary Implants. Arch. Pathol., 82: 425-429, 1966. 12. Heston, W. E. Mammary Tumors in Agent-free Mice. Ann. N. Y. Acad. Sci., 71: 931-942, 1957-1958. 13. Hoffman, W. S. A Rapid Photoelectric Method for the Determination of Glucose in Blood and Urine. J. Biol. Chem., 120: 51-55, 1937. 14. Huseby, R. A., and Bittner, J. J. A Comparative Morphological Study of the Mammary Glands with Reference to the Known Factors Influencing the Development of Mammary Carcinoma in Mice. Cancer Res., 6: 240-255, 1946. 15. Katz, J., and Wood, H. G. The Use of 14CO2 Yields from Glucose-l-"C and -6-""C for the Evaluation of the Pathways of Glucose Metabolism. J. Biol. Chem., 238: 517-523, 1963. 16. LeRoy, G. V., Okita, G. T., Tocus, E. C., and Charleston, D. CANCER RESEARCH VOL. 31 Downloaded from cancerres.aacrjournals.org on August 2, 2017. © 1971 American Association for Cancer Research. Glucose Metabolism in C3H Mice Continuous Measurements of Specific Activity of 14CO2 in Expired air. Intern. J. Appi. Radiation Isotopes, 7: 273-286, 1960. 17. Nandi, S. Interactions among Hormonal, Viral, and Genetic Factors in Mouse Mammary Tumorogenesis. Can. Cancer Conf. 6: 69-81, 1966. 18. Okita, G. T. In Vivo Oxidation of C1'-Labeled Intermediates and of Drugs as Measured by a Continuous C'4O2 Monitor./«: L. J. Roth (ed.), Isotopes in Experimental Pharmacology, pp. 191-203. Chicago: The University of Chicago Press, 1965. 19. Okita, G. T., and Ezz, E. A. Biochemical Studies on Spontaneous Carcinogenesis: in Vivo Effects of Hormonal Changes on C3H Mice Bearing Hormone-dependent Mammary Carcinoma. Acta Unió Intern. Contra Cancrum, 20: 1463-1467, 1964. DECEMBER 1971 Downloaded from cancerres.aacrjournals.org on August 2, 2017. © 1971 American Association for Cancer Research. 1961 Effect of Mammary Tumor Virus Infection on in Vivo Oxidation of Glucose-1- 14C and Glucose-6-14C in C3H Mice Hans R. Burki and George T. Okita Cancer Res 1971;31:1955-1961. 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