Biomedical subjects

C W Song

Publications and source records attributed to C W Song.

At least 19 recordsLinked to original sources

PubMed1992

Ionizing radiation stimulates unidentified tyrosine-specific protein kinases in human B-lymphocyte precursors, triggering apoptosis and clonogenic cell death.

Very little is known regarding the effects of ionizing radiation on cytoplasmic signal transduction pathways. Here, we show that ionizing radiation induces enhanced tyrosine phosphorylation of multiple substrates in human B-lymphocyte precursors. This response to ionizing radiation was also observed in cells pretreated with vanadate, a potent protein-tyrosine-phosphatase (PTPase) inhibitor, and phosphotyrosyl [Val5]angiotensin II phosphatase assays showed no decreased PTPase activity in irradiated cells. Thus, enhanced tyrosine phosphorylation in irradiated B-lymphocyte precursors is not triggered by inhibition of total cellular PTPase activity. Immune-complex kinase assays using anti-phosphotyrosine antibodies demonstrated enhanced protein-tyrosine kinase (PTK) activity in the immunoprecipitates from irradiated cells, and the PTK inhibitors genistein and herbimycin effectively prevented radiation-induced tyrosine phosphorylation. Immune-complex kinase assays on irradiated and unirradiated B-lymphocyte precursors using antibodies prepared against unique amino acid sequences of p59fyn, p56/p53lyn, p55blk, and p56lck demonstrated that these Src-family tyrosine kinases were not the primary PTKs responsible for enhanced tyrosine kinase activity in the anti-phosphotyrosine antibody immunoprecipitates or for enhanced tyrosine phosphorylation of multiple substrates. Thus, our findings favor the hypothesis that ionizing radiation induces enhanced tyrosine phosphorylation in B-lymphocyte precursors by stimulation of as yet unidentified PTKs. Tyrosine phosphorylation appears to be an important proximal step in radiation-induced apoptosis and clonogenic cell death because inhibition of PTK prevents DNA fragmentation and loss of clonogenicity of irradiated B-lymphocyte precursors. Since PTKs play myriad roles in the regulation of cell function and proliferation, the activation of a PTK cascade, as detailed in this report, may explain some of the pleiotropic effects of ionizing radiation on cellular functions of B-lymphocytes and their precursors.

Apoptosis↗

PubMed1992

Radiation and heat sensitivity of human T-lineage acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) clones displaying multiple drug resistance (MDR).

The hyperthermia as well as radiation responses of multidrug resistant (CEM/VLB100 with classical MDR and CEM/VM-1 with atypical MDR), methotrexate resistant (CEM/MTX) subclones of CCRF-CEM T-lineage ALL cell line were compared with those of a drug sensitive (CEM-1-3) subclone from the same parent cell line. Also analyzed were the hyperthermia as well as radiation responses of multidrug resistant (HL60/AR) and drug sensitive subclones of the HL60 AML cell line. Notably, the drug resistant subclones of CEM and HL60 were as sensitive to hyperthermia as were the drug sensitive subclones. Importantly, no thermotolerant plateau was observed in the hyperthermia survival curves of the drug resistant subclones, indicating that drug/multidrug resistance is not associated with a greater likelihood of thermal tolerance development during hyperthermia. Similarly, the drug resistant CEM and HL60 subclones were not more radiation resistant than the drug sensitive subclones. Thus, the classical or atypical forms of multidrug resistance or methotrexate resistance of the analyzed leukemic cell lines were not associated with radiation resistance. Furthermore, the radiation survival curves of the drug resistant subclones lacked a distinct initial shoulder and their n values were not greater than those of the drug sensitive subclones, suggesting that multidrug resistance is not associated with an increased ability to repair or accumulate sublethal radiation damage. Our findings provide evidence that there is no apparent association between drug/multidrug resistance and heat or radiation sensitivity of CEM T-lineage ALL or HL60 AML leukemia cells. The results of this study indicate that acquired resistance to methotrexate, vinblastine, vincristine, etoposide, actinomycin-D, adriamycin, or daunomycin, or pleiotropic multidrug resistance do not necessarily confer radiation resistance for human leukemic cells.

Adaptation, Physiological↗

PubMed1992

Immunophenotype predicts radiation resistance in T-lineage acute lymphoblastic leukemia and T-lineage non-Hodgkin's lymphoma.

In the preclinical arm of our study, the radiobiologic features of primary malignant cells from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia/non-Hodgkin's lymphoma patients were analyzed using clonogenic assays. A marked heterogeneity existed relative to the intrinsic radiation sensitivity of clonogenic T-lineage ALL/NHL cells from 42 patients. The mean SF2 (surviving fraction at 200 cGy) and alpha values (initial slope of the survival curve) were 0.36 +/- 0.04, and 0.558 +/- 0.079 Gy-1. Fourteen cases had SF2 values of > or = 0.50 and alpha values of < or = 0.2 Gy-1, consistent with a marked intrinsic radiation resistance at the level of clonogenic leukemia/lymphoma cells. Of these 14 radiation resistant cases, 12 were CD3+. Furthermore, the SF2 and D0 values of the 28 CD3+ cases were significantly higher than the SF2 and D0 values of the 14 CD3- cases (SF2: 0.441 +/- 0.048 versus 0.189 +/- 0.045, p = 0.002; D0: 189.6 +/- 26.3 cGy versus 108.7 +/- 18.2 cGy, p = 0.047) and CD3+ cases had smaller alpha values than CD3- cases (0.454 +/- 0.087 versus 0.765 +/- 0.152, p = 0.06). Thus, clonogenic cells from CD3+ T-lineage ALL/NHL patients were more resistant to radiation than clonogenic cells from CD3- T-lineage ALL/NHL patients. In the clinical arm of our study, 33 T-lineage ALL/NHL patients received autologous bone marrow transplants during remission. Pretransplant conditioning consisted of total body irradiation combined with high dose chemotherapy. The expression of CD3 antigen predicted the outcome of relapsed T-lineage ALL/NHL patients undergoing autologous bone marrow transplantation following total body irradiation plus high dose chemotherapy. Overall, the Kaplan-Meier estimate and standard error of the probability of remaining in remission at 3.5 years was 11 +/- 9% with a median relapse-free interval of 102 days. The disease-free survival at 3.5 years was 8 +/- 7% with a median disease-free survival time of 96 days. Notably, the expression of CD3 antigen on T-lineage ALL/NHL cells correlated with the probability of relapse after bone marrow transplantation. While 16 of 19 CD3+ patients relapsed after bone marrow transplantation, only 3 of 8 CD3- patients relapsed. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission at 1 year after bone marrow transplantation were 7 +/- 6% (median relapse-free interval = 74 days) for CD3+ patients (n = 19) and 63 +/- 17% for CD3- patients (n = 8) (p = 0.006).(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Line↗

PubMed1992

Increases in tumor response by pentoxifylline alone or in combination with nicotinamide.

Pentoxifylline (PENTO), a derivative of methylxanthine, has been reported to improve fluidity of red blood cells (RBC), and thus improve the flux of RBC through narrow capillaries. Additionally, PENTO increases 2,3-DPG levels in RBC, thereby increasing the O2 release from RBC. Nicotinamide (NA) has been known to increase tumor blood flow, reducing the hypoxic cell fractions in the tumors. The purpose of this study was to examine the effects of PENTO alone or in combination with NA (PENTO + NA) on the oxygenation and radio-response of FSaII murine fibrosarcomas of mice. We observed a significantly enhanced, radiation-induced growth delay of the FSaII tumors by the treatment of either single or multiple injections of PENTO. The combination of PENTO and NA further delayed the growth of tumors. The TCD50 of control tumors was about 56.6 Gy, whereas that of PENTO + NA treated tumors was about 31.9 Gy. Thus, TCD50 was modified by a factor of 1.8. PENTO + NA exerted no effect on the acute skin damage of C3H mice after local irradiation and the gastrointestinal death after whole body irradiation. However, PENTO + NA slightly increased the bone marrow death as demonstrated by the decrease in LD50(30) from 5.5 Gy to 5.2 Gy. The average pO2 in the saline-treated control group of FSaII tumors was 8 mmHg and it significantly increased to 19 mmHg in the PENTO + NA treated group (p less than 0.001). We concluded that the PENTO + NA treatment increased the radio-response of tumors by improving tumor oxygenation.

Animals↗

PubMed1992

Relationship between vascular thermotolerance and intratumor pH.

The changes in blood flow, intratumor pH, and clonogenicity of tumor cells after one and two heatings were studied in SCK tumors of A/J mice. When SCK tumors were heated at 42.5 degrees C for 1 hr, vascular thermotolerance promptly developed and peaked at 18 hr post-heating. The intratumor pH was 7.05 +/- 0.14 (mean +/- S.D.) in control SCK tumors of A/J mice, with a significant decrease (p less than or equal to 0.001) to 6.86 +/- 0.08 and 6.70 +/- 0.08 when heated for 1 hr at 43.5 degrees C and 44.5 degrees C, respectively. However, when the vascular thermotolerance was at its peak, heating at the same doses caused little change in the intratumor pH. When SCK tumors were heated for the first time at 44.5 degrees C for 1 hr and left in situ, the number of clonogenic cells significantly declined. Such a secondary cell death could be attributed to the deterioration of the intratumor environment ensuing from the vascular damage. When the tumor vessels were thermotolerant, however, virtually no secondary cell death occurred after heating.

Animals↗

PubMed1992

The oxygenation of murine tumor isografts and human tumor xenografts by nicotinamide.

The changes in pO2 caused by nicotinamide in the FSaII mouse tumor and three different xenografts of human tumors, HP-56, FaDu, and EO1, grown subcutaneously in the legs of mice were studied. The tumor pO2, as measured with microelectrodes, began to rise soon after the host mice were injected intraperitoneally with 500 mg/kg nicotinamide, and it increased continuously for 100-120 min. The rate and magnitude of the increase in tumor pO2 was dependent on the tumor line and also on the tumor size. In FSaII tumors, the increase in pO2 caused by nicotinamide was relatively small in the well-oxygenated small tumors (173 +/- 5 mm3) compared with that in the larger tumors (515 +/- 25 mm3). The blood perfusion in FSaII tumors as measured with the laser Doppler method was also increased by nicotinamide. The growth delay in FSaII tumors induced by X irradiation was enhanced significantly by nicotinamide. It was concluded that the enhancement of radiation damage in the experimental tumors in mice by nicotinamide, as observed in the present study and reported by others, is due to an increase in intratumor pO2, possibly as a result of an increase in blood perfusion.

Animals↗

PubMed1992

Increase in tumor oxygenation and radiosensitivity caused by pentoxifylline.

The effects of pentoxifylline (PTX), a drug commonly used for vascular disorders in humans, on the pO2 in SCK tumors of A/J mice and FSa-II tumors of C3Heb/FeJ mice as well as on the radioresponse of SCK tumors were investigated. When the host mice were injected intraperitoneally (ip) with 5 mg/kg PTX, the tumor pO2 increased slowly, peaked 20-50 min postinjection, and returned to its original level in 70-90 min. The magnitude of the increase in tumor pO2 varied markedly depending on the site and tumors. The magnitude of the changes in tumor pO2 after an ip injection of 25 or 50 mg/kg PTX was similar to that caused by 5 mg/kg PTX, but the pO2 tended to remain elevated longer with the higher dose of PTX. When the A/J mice bearing SCK tumors in the legs were injected ip with 50 mg/kg PTX and the tumors were X-irradiated 20 min later, the radiation-induced growth delay of the tumors was greater than that caused by X irradiation alone. The present study demonstrated that PTX is potentially useful for increasing the pO2 and the radioresponse of human tumors.

Animals↗

PubMed1992

Modification of intracellular pH and thermosensitivity.

The effects of amiloride (an inhibitor of Na+/H+ antiport), DIDS (an inhibitor of Na(+)-coupled and Na(+)-independent HCO3-/Cl- exchange) and nigericin (K+/H+ ionophore) alone and in various combinations on the intracellular pH (pHi) and thermosensitivity of SCK tumor cells were studied. Hyperthermia alone at 43 degrees C for 2 h decreased pHi of SCK cells by 0.15-0.20 pH units, as measured fluorometrically using the pH-sensitive dye BCECF. When the cells were treated with 0.5 mM amiloride at 37 degrees C, the pHi declined by 0.10-0.15 pH units at an extracellular pH (pHe) of both 7.2 and 6.6. Amiloride at 0.5 mM enhanced the thermal damage to SCK cells at pHe 6.6 but not at pHe 7.2. DIDS alone at 0.1 mM exerted no effect on pHi or cellular thermosensitivity. DIDS, however, enhanced the effects of amiloride in decreasing pHi and in increasing the thermoresponse of SCK cells, particularly at pHe 6.6. Treatment of the cells with nigericin at 0.1-1.0 micrograms/ml lowered the pHi and enhanced the thermosensitivity of the cells in a dose-dependent manner. Reductions in pHi and increases in thermosensitivity by nigericin at the lower concentration at pHe 6.6 were far greater than at pHe 7.2. When a mixture of 1.0 micrograms/ml nigericin, 0.5 mM amiloride, and 0.1 mM DIDS was present in the medium, the pHi rapidly decreased by about 0.3 and 0.4 pH units at pHe 7.2 and 6.6, respectively. This drug combination was also extremely effective in sensitizing SCK cells to heat, particularly at pHe 6.6. The fact that the thermosensitization by these drugs at pHe 6.6 is more pronounced than at pHe 7.2 and that intratumor environments are known to be acidic strongly suggested that it may then be possible to enhance the thermal damage with such drugs preferentially in tumors relative to normal tissues.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1991

In vitro and in vivo radiation resistance associated with CD3 surface antigen expression in T-lineage acute lymphoblastic leukemia.

The radiobiologic features of primary clonogenic blasts (referred to also as T-lineage leukemic progenitor cells) from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia (ALL) patients were analyzed. Intrinsic radiation sensitivity differed substantially among primary clonogenic blasts from 34 newly diagnosed patients. The mean D0 (37% dose slope), SF2 (surviving fraction at 200 cGy), and alpha values (initial slope of the survival curve) were 141 +/- 15 cGy, 0.31 +/- 0.04, and 0.630 +/- 0.093 Gy-1, respectively. Among newly diagnosed cases, nine had SF2 values of greater than or equal to 0.50 and alpha values of less than or equal to 0.2 Gy-1, consistent with a marked intrinsic radiation resistance at the level of clonogenic blasts using the multitarget and linear quadratic models of cell survival. Of these nine radiation resistant cases, seven were CD3+. Furthermore, the mean D0 (162 +/- 20.8 cGy) and SF2 (0.377 +/- 0.057) values for the 20 CD3+ cases were significantly higher than the D0 (108.6 +/- 18.2 cGy) and SF2 (0.204 +/- 0.051) values for the 14 CD3- cases (P less than or equal to .05). Thus, clonogenic blasts from CD3+ newly diagnosed T-lineage ALL patients were more resistant to radiation than clonogenic blasts from CD3- newly diagnosed T-lineage ALL patients. Nineteen T-lineage ALL patients received autologous bone marrow transplants during complete remission. Pretransplant conditioning consisted of total body irradiation (TBI) combined with high-dose chemotherapy. Primary clonogenic blasts from patients who relapsed after bone marrow transplantation (BMT) displayed a particularly high degree of intrinsic radiation resistance with a mean D0 value of 333 cGy and an alpha value of 0.112 Gy-1. The expression of CD3 antigen appeared to predict the outcome of relapsed T-lineage ALL patients undergoing autologous BMT after TBI plus high-dose chemotherapy. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission after BMT were 60% +/- 22% (mean relapse - free interval = 1.6 +/- 0.7 years) for CD3- patients and 0% +/- 0% (mean relapse - free interval = 0.2 +/- 0.0 years) for CD3+ patients (P = .002). Furthermore, the mean percentage of CD3-positive leukemic marrow blasts at presentation or relapse before BMT was significantly lower than the mean percentage of CD3-positive leukemic marrow blasts at relapse after BMT. Notably, in cultured leukemic bone marrow specimens from newly diagnosed as well as relapsed patients, colony blasts surviving in vitro radiation expressed CD3 more vividly than did colony blasts in unirradiated cultures.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1991

Comparative analysis of the in vivo radioprotective effects of recombinant granulocyte colony-stimulating factor (G-CSF), recombinant granulocyte-macrophage CSF, and their combination.

The purpose of the present study was to evaluate and compare the in vivo radioprotective effects of pre-total body irradiation (TBI) conditioning with recombinant granulocyte colony-stimulating factor (rG-CSF) and recombinant granulocyte-macrophage CSF (rGM-CSF) in a large series of lethally and supralethally irradiated mice. Also analyzed were the radioprotective effects of simultaneous as well as sequential combinations of rG-CSF and rGM-CSF. Our findings in 1,180 mice provide direct evidence that in vivo administration of rG-CSF or rGM-CSF before TBI protects a significant fraction of mice from the lethal effects of LD100/30 TBI. At equivalent doses, rG-CSF displayed a more potent radioprotective activity than rGM-CSF. Not only was rG-CSF radioprotective at much smaller doses than rGM-CSF, the survival rate after lethal TBI was also significantly higher in mice receiving optimally radioprotective doses of rG-CSF as compared with mice receiving optimally radioprotective doses of rGM-CSF. Pretreatment of mice with rGM-CSF markedly attenuated the radioprotective affects of rG-CSF in lethally as well as supralethally irradiated mice. Pretreatment with rG-CSF followed by rGM-CSF was slightly more effective than rG-CSF alone in supralethally irradiated mice but not in lethally irradiated mice. Notably, marked differences among different strains of mice were noted regarding the optimally radioprotective doses of rG-CSF or rGM-CSF as well as probability of survival and median survival time after lethal or supralethal TBI. This report confirms and extends previous studies concerning the potential of cytokines in prevention or therapy of lethal radiation injury.

Animals↗

PubMed1991

Effects of amiloride on intracellular pH and thermosensitivity.

Amiloride, a diuretic drug, is a potent inhibitor of Na+/H+ exchange through the plasma membrane, and has been reported to enhance thermal damage in tumor cells in vitro. We investigated the possible relationship between changes in the thermal response of SCK mouse mammary tumor cells in vitro and changes in intracellular pH (pHi) due to amiloride in the present study. At a concentration of 0.5 mM, amiloride reduced the shoulder (Dq) without causing significant change in the slope (Do) of the survival curve of SCK cells heated once at 43 degrees C. On the other hand, 0.5 mM of amiloride sensitized thermotolerant cells to heat as shown by a reduction in Do. The presence of amiloride during the interval between the first and second heatings slightly reduced or inhibited the development of thermotolerance. The pHi was measured with the BCECF fluorescence method. The presence of 0.5 mM amiloride significantly reduced pHi in both pH 7.2 and 6.6 medium. Heating the SCK cells at 43 degrees C in pH 7.2 or 6.6 medium also reduced the pHi. The combined effect of heat and amiloride in reducing the pHi of SCK cells was additive. These results suggest that the effects of amiloride on the thermal response of SCK cells might be mediated in part by a decrease in pHi. The possibility that the effects of amiloride on the thermal response of tumor cells are mediated by other biochemical changes, such as inhibition of protein synthesis, however, could not be ruled out.

Amiloride↗

PubMed1991

Effect of hydralazine on the blood flow in tumors and normal tissues in rats.

The effects of hydralazine on the blood flow in various normal tissues and R3230 Ac adenocarcinomas grown in different sites in rats were studied. Tumors were induced in the kidney, liver, and flank (s.c.) by injection of small pieces of tumors. Tumors were also induced in small intestine, cecum, and mesentery by intraperitoneal injection of finely minced tumor tissue. The blood flow and cardiac output were measured by radioactive microsphere method. An intra-arterial injection of hydralazine at 2.5-10.0 mg/kg significantly reduced the blood flow in most normal tissues, whereas it markedly increased the blood flow in muscle. The blood flow in the brain and testes remained unchanged. The blood flow in the tumors varied depending on the tumor site and was markedly smaller than the blood flow in the host normal tissues in which the tumors grew. The blood flow in tumors decreased significantly upon injection of hydralazine except in the tumors grown in the liver, where the blood flow remained unchanged. The hydralazine injection slightly increased cardiac output and markedly decreased blood pressure. It appeared that the decreases in blood flow by hydralazine in the tumors and most normal tissues were caused mainly by diversion of blood to muscle, resulting in a marked increase in the muscle blood flow without a similar concomitant increase in cardiac output. The results obtained in the present study indicate that hydralazine may be useful for improving the efficacy of hyperthermia or for enhancing the toxicity of hypoxic cell specific bioreductive drugs in treating the tumors grown in skeletal muscle. However, the significant decline in blood flow in most normal tissues may pose potential problems in the use of hydralazine to enhance the effect of hyperthermia or bioreductive drugs on tumors grown in normal tissues other than muscle.

Adenocarcinoma↗

PubMed1991

Precooling prevents overheating of subcutaneous fat in the use of RF capacitive heating.

The usefulness of precooling subcutaneous tissue in the hyperthermic treatment of deep-seated human tumors with capacitive application of radio-frequency (RF) was investigated. A capacitive hyperthermia unit operated at 8 MHz of radiofrequency was used to heat deep-seated human tumors. The electrode surfaces were covered with flexible vinyl sheets and the space between the electrode and the vinyl sheets perfused with 0.4% saline. The temperature of the saline was controlled by circulating the saline through built-in heat exchangers. The depth of heating was controlled by pairing electrodes of different diameters. When subcutaneous fat was less than 1 cm thick, various deep-seated tumors could be heated to a therapeutic temperature without significant discomfort in the subcutaneous tissue as long as the skin was properly cooled with the cold saline bolus. However, the same cooling method could not prevent the occurrence of pain in subcutaneous tissue in obese patients. The pain usually developed when the temperature of subcutaneous fat 1-2 cm below the skin surface exceeded 42 degrees C. We observed that cooling the human skin surface with 10 degrees C bolus for 20 min could substantially lower the temperature of fat as deep as 2.0-2.5 cm. Therefore, when the subcutaneous tissue was precooled with 10 degrees C saline for 20 min or longer before heating, it was possible to prevent successfully the overheating of subcutaneous fat as thick as 2.0-2.5 cm and to raise the temperature of deep-seated tumors to therapeutic levels.

Adipose Tissue↗

PubMed1991

Radiation sensitivity of human B-lineage lymphoid precursor cells.

We studied the radiation sensitivity of eight immunophenotypically distinct B-lineage lymphoid precursor cell (LPC) lines of acute lymphoblastic leukemia (ALL) or fetal liver origin corresponding to discrete developmental stages of human B-cell ontogeny. The radiation sensitivity of B-lineage LPC showed a temporal association with the distinct stages of development. FL112 and FL114 fetal liver pro-B cells (Stage 0 B-lineage LPC) with germline immunoglobulin heavy chain (IgH) genes but rearranged T-cell receptor gamma (T gamma) genes (DO of FL112 = 80.3 cGy, DO of FL114 = 50.2 cGy), REH ALL pre-pre-B cells (Stage I B-lineage LPC) with rearranged IgH and T gamma genes (DO = 66.1 cGy), and NALM-6 ALL pre-pre-B/pre-B cells (Stage II B-lineage LPC) (DO = 50.5 cGy) corresponding to the earliest three stages of human B-lymphocyte development were the most radiation sensitive B-lineage LPC populations. By comparison, KM-3 ALL pre-B (Stage III B-lineage LPC) (DO = 194.7 cGy), HPB-NULL ALL pre-B (Stage IV B-lineage LPC) (DO = 134.6 cGy), and sIgM+ RAJI/NAMALWA early B (Stage Va/b B-lineage LPC) cell lines (DO of RAJI = 144.0 cGy, DO of NAMALWA = 165.5 cGy) corresponding to the later stages of human B-lymphocyte development were much more radiation resistant. These results indicate that the radiation sensitivity of B-lineage LPC decreases during maturation within the B-lineage lymphoid precursor pathway. By comparison, the S-phase index (% of S-phase cells as determined by DNA flow cytometry) or proliferation index (% S + G2M), cellular protein content, intracellular glutathione (GSH) level, glutathione-S-transferase (GST) activity, intracellular pH, or free cytoplasmic calcium concentration did not correlate with the radiation sensitivity of the B-lineage LPC.

B-Lymphocytes↗

PubMed1991

Regulation of pH in murine tumor and muscle.

The relationship between intracellular and extracellular pH was investigated in a murine tumor and normal tissue, prior to and following glucose injection. Isotransplants of the murine tumor FSa-II in the dorsum of the hind foot and leg muscle, were investigated in nonanesthetized mice. Extracellular pH was measured with a glass microelectrode, with a tip diameter of approximately 80 microns. Intracellular pH was evaluated by 31P-NMR spectroscopy, using a wide-bore NT-150 spectrometer operating at 60.75 MHz. Five grams per kilogram intraperitoneal glucose led to small changes in extracellular pH of muscle (-0.13 unit) measured with a microelectrode, and no change in intracellular pH measured by NMR. In contrast, tumor intracellular pH decreased by 0.34 units and tumor extracellular pH by 1.13 units. The differential effect of glucose on tumor vs normal tissue, and pronounced pH gradient which develops in tumor cells should markedly affect the intracellular:extracellular distribution of drugs which are weak acids or bases.

Animals↗

PubMed1990

Changes in intratumor pH by two heatings.

It is a known fact that pH in rodent tumors decline significantly upon heating most likely due to breakdown of the tumor blood circulation. We recently observed that tumor blood vessels become thermotolerant after being heated with a sublethal thermal dose. The purpose of the present study was to reveal whether heating can reduce intratumor pH when the tumor vessels are thermotolerant. When the SCK tumors of A/J mice were heated at 42.5 degrees C for 1 h, the tumor vessels became most thermotolerant at 18 h postheating, as measured with the 86Rb uptake method. The intratumor pH in the control SCK tumors was 7.05 +/- 0.14 (SD), and it significantly decreased to 6.70 +/- 0.08 (P less than 0.001) after heating at 44.5 degrees C for 1 h. However, when the tumor vessels were thermotolerant, i.e., 18 h after heating at 42.5 degrees C for 1 h, reheating at 44.5 degrees C for 1 h could not reduce the intratumor pH. We concluded that such a failure to increase tumor acidity by a second heating at temperatures as high as 44.5 degrees C was due to vascular thermotolerance developed by the first heating.

Animals↗

PubMed1990

In vivo radioprotective effects of recombinant human granulocyte colony-stimulating factor in lethally irradiated mice.

The purpose of this study was to investigate the in vivo radioprotective effects of recombinant human granulocyte colony stimulating factor (rhG-CSF) in lethally irradiated BALB/c mice. We initially analyzed the effects of increasing doses of rhG-CSF on survival of mice receiving 700 cGy (LD100/30) single dose total body irradiation (TBI). While 1 microgram/kg to 100 micrograms/kg doses of rhG-CSF were not radioprotective, a dose-dependent radioprotection was observed at 200 micrograms/kg to 4,000 micrograms/kg rhG-CSF. We next compared four different rhG-CSF treatment regimens side by side for their radioprotective effects in LD100/30 irradiated mice. One hundred percent of control mice receiving phosphate buffered saline died within 21 days after TBI with a median survival of 14 days. The median survival was prolonged to 20 days and the actuarial 60-day survival rate was increased to 27% when mice received 2,000 micrograms/kg rhG-CSF 24 hours before TBI (P = .0002; Mantel-Peto-Cox). Similarly, the median survival time was prolonged to 24 days and the actuarial 60-day survival rate was increased to 33%, when mice were given 2,000 micrograms/kg rhG-CSF 30 minutes before TBI. Optimal radioprotection was achieved when 2,000 micrograms/kg rhG-CSF was administered in two divided doses of 1,000 micrograms/kg given 24 hours before and 1,000 micrograms/kg given 30 minutes before TBI. This regimen prolonged the median survival time of LD100/30 irradiated mice to more than 60 days and increased the actuarial 60-day survival rate to 62% (P = .0001; Mantel-Peto-Cox). By comparison, no survival advantage was observed when mice received rhG-CSF 24 hours post-TBI. Similar radioprotective effects were observed when mice were irradiated with 650 cGy (LD80/30). The presented findings provide conclusive evidence that rhG-CSF has significant in vivo radioprotective effects for mice receiving LD100/30 or LD80/30 TBI.

Animals↗

PubMed1990

Pathophysiological changes after local heating of rat liver.

Changes in blood flow in rat liver by local heating of the left lateral lobe were studied. A small portion of the left lateral lobe was heated by capacitive application of 8 MHz RF with a 2 cm diameter electrode on the ventral surface and a 7 cm diameter electrode on the dorsal surface of upper body of rats. A circular area with diameter of about 1 cm in the left lateral lobe could be heated to relatively homogeneous temperatures. The temperature in the remaining part of the left lateral lobe as well as in the rest of liver tissue also increased to varying degrees during the local heating of the left lateral lobe. When heated at 39 degrees or 41 degrees C for 45 min, the arterial blood flow, as measured with the radioactive microsphere method, in the heated area, and that in the rest of the left lateral lobe as well as in the whole liver initially increased during the first 30 min and then started to decline. During a 45 min heating at 43 degrees C, the arterial blood flow in the heated area slightly increased for 15 min and then significantly decreased thereafter. The arterial blood flow in the rest of the liver tissue also increased during the first 15 min of a 43 degrees C heating and began to decline. Histological examination of liver heated at 43 degrees C for 30 min showed wedge-shaped infarctions early on, which appeared to be organized into scar tissue by 7 days after heating. The concentrations of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) in the serum significantly increased 2 hr after heating the small portion of the left lateral lobe at 43 degrees C for 30 min and began to decrease thereafter although the serum level of GOT and GPT was still greater than the control value 24 hr after heating.

Alanine Transaminase↗