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C W Song

Publications and source records attributed to C W Song.

At least 73 records · Page 4Linked to original sources
PubMed1994

Roles of gut hormones in negative-feedback regulation of pancreatic exocrine secretion in humans.

BACKGROUND/AIMS: Secretin has been shown to mediate feedback control of pancreatic secretion of fluid and bicarbonate in rats, guinea pigs, and dogs. However, little is known about secretin in the feedback regulation in humans. We investigated the roles of secretin, cholecystokinin, neurotensin, and pancreatic polypeptide on feedback regulation of pancreatic secretion in 10 human volunteers. METHODS: A 5-lumen tube was positioned in the proximal jejunum of fasting subjects under fluoroscopy so that gastric juice via lumen 1 and duodenal contents via lumen 3 were collected separately in 15-minute samples while polyethylene glycol solution was infused into duodenum via lumen 2. An acidified (pH 2.0) 4.25% amino acid mixed with phenol red was infused into proximal jejunum via lumen 4, which was alternated with NaHCO3 (control solution) or trypsin (test solution) via lumen 5 intermittently every 15 minutes during separate test periods. RESULTS: Infusion of control solution significantly increased both bicarbonate (total change [delta], 7799 +/- 1400 mumol/h) and chymotrypsin (delta 5500 +/- 762 mumol/h) outputs and levels of all four plasma hormones. The test solution significantly inhibited both bicarbonate (delta 2999 +/- 700 mumol/h; P < 0.01) and chymotrypsin output (delta 1000 +/- 120 U/h, P < 0.01), which coincided with a significant suppression of plasma concentration of secretin and cholecystokinin but not pancreatic peptide and neurotensin. CONCLUSIONS: A negative-feedback regulation of pancreatic secretion of bicarbonate and enzyme occurs in humans and is mediated via both secretin and cholecystokinin.

Adolescent↗
PubMed1994

Esophageal duplication cyst complicated with intramural hematoma--case report.

Esophageal duplication cysts account for a very small percentage of benign esophageal tumors and are infrequently symptomatic. Esophageal duplication cysts result from aberrant alignment of the normal vacuolization process that produce the esophageal lumen in the 5th to 8th week of embryonic life. Complications most often are bleeding into or infection of cysts. Recently, we experienced a case of esophageal duplication cyst complicated with intramural huge hematoma and the cause of hematoma could not be identified. We report it with a review of literatures.

Esophageal Cyst↗
PubMed1993

Radiation resistance of primary clonogenic blasts from children with acute lymphoblastic leukemia.

PURPOSE: Detailed comparative analyses of the radiation sensitivity of primary clonogenic blasts from children with acute lymphoblastic leukemia (ALL) were performed to achieve a better understanding of clinical radiation resistance in ALL. METHODS AND MATERIALS: The radiation sensitivity of primary clonogenic blasts from 74 children with newly diagnosed acute lymphoblastic leukemia (ALL) was analyzed using leukemic progenitor cell (LPC) assays. Primary bone marrow blasts from all 74 patients were exposed to ionizing radiation and subsequently assayed for LPC-derived blast colony formation. Radiation survival curves of primary clonogenic blasts (i.e., LPC) were constructed for each of the newly diagnosed patients using computer programs for the single-hit multitarget as well as the linear quadratic models of cell survival. RESULTS: A marked interpatient variation in intrinsic radiation sensitivity was observed between LPC populations. The SF2 values ranged from 0.01 to 1.00 (median: 0.36; mean +/- SE = 0.40 +/- 0.03), and the alpha values ranged from 0.00 Gy-1 to 3.27 Gy-1 (median: 0.280 Gy-1; mean +/- SE = 0.43 +/- 0.09 Gy-1). Patients were divided into groups according to their sex, age, WBC at diagnosis, cell cycle distribution of leukemic blasts, and immunophenotype. Only immunophenotype provided a significant correlation with the intrinsic radiation sensitivity of LPC. Patients with B-lineage ALL had higher SF2 (0.47 +/- 0.04 vs. 0.31 +/- 0.05, p < 0.05) and smaller alpha values (0.43 +/- 0.09 Gy-1 vs. 0.65 +/- 0.10 Gy-1, p < 0.05) than T-lineage ALL patients, consistent with greater intrinsic radiation resistance at the level of LPC. Notably, 43% of B-lineage ALL cases, but only 27% of T-lineage ALL cases had LPC with SF2 > or = 0.5. Similarly, 66% of B-lineage ALL cases, but only 37% of T-lineage ALL cases had LPC with alpha values < or = 0.4 Gy-1. Combining the two indicators of radiation resistance, we found that only 34% of the B-lineage ALL patients had none of the two parameters in the respective critical regions (alpha < or = 0.4 Gy-1; SF2 > or = 0.5), while 63% of the T-lineage patients had none (p < 0.05). In multivariate analyses, the immunophenotypic B-lineage affiliation was the only significant predictor of radiation resistance at the level of LPC. Whether alone or in combination, none of the other variables examined, including sex, age, WBC, in vitro plating efficiency, S-phase index, and proliferation index were significantly correlated with the radiation sensitivity or resistance of LPC. CONCLUSION: These results offer unprecedented evidence for an association between composite immunophenotype (viz., B-lineage ALL vs T-lineage ALL) and radiation resistance that may form a basis for modifying radiation conditioning regimens.

Adolescent↗
PubMed1993

Influence of vascular thermotolerance on the heat-induced changes in blood flow, pO2, and cell survival in tumors.

Vascular thermotolerance in SCK tumors of A/J mice was studied by comparing the changes in blood flow, as measured by the 86Rb uptake method, from a single heating with those from two heatings. The heat-induced decline in 86Rb uptake in tumors could be substantially inhibited when the tumors were preheated, indicating the development of vascular thermotolerance. In SCK tumors, the vascular thermotolerance peaked 5 or 18 h after the tumors were heated for 1 h at 41.5 degrees C or 42.5 degrees C, respectively. Consequently, the tumor blood flow decreased by 50% in 81 min when the tumors were heated at 43.5 degrees C without preheating, whereas the tumor blood flow decreased by 50% in 195 min at 43.5 degrees C when the tumors were preheated 18 h earlier at 42.5 degrees C for 1 h. The influence of vascular thermotolerance on the heat-induced changes in intratumor pO2 was also investigated. The average intratumor pO2 was 8.9 mm Hg before heating. Heating at 43.5 degrees C or 44.5 degrees C for 1 h dramatically decreased the intratumor pO2 to 3.0 or 1.2 mm Hg, respectively. However, the intratumor pO2 decreased to 6.6 or 3.8 mm Hg when the tumors were heated at 43.5 degrees C or 44.5 degrees C, respectively, 18 h after preheating at 42.5 degrees C for 1 h. Heating the tumors when tumor vasculatures were at peak thermotolerance was relatively ineffective in suppressing tumor growth. The data demonstrate that vascular thermotolerance in tumors may exert profound effects on tumor response to multiple heatings in clinical hyperthermia.

Animals↗
PubMed1993

Increase in thermosensitivity of tumor cells by lowering intracellular pH.

We previously reported that the thermosensitivity of tumor cells can be increased when the intracellular pH is lowered by inhibiting Na+/H+ exchange through the plasma membrane with amiloride (3,5-diamino-6-chloro-N-(diamino methylene)pyrazinecarboxamide) or its analogues and HCO3-/Cl-exchange with 4,4-diiothiocyanato-stilbene-2,2'-disulfonic acid. In this study, we investigated the effects of (3-amino-6-chloro-5- (1-homopiperidyl)-N-(diaminomethylene)pyrazine-carboxamide) (HMA), an analogue of amiloride and a potent inhibitor of Na+/H+ exchange, and R(+)-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren -7- yl)oxy]acetic acid [B-3(+)], a potent inhibitor of HCO3-/Cl- exchange, on the thermosensitivity of SCK tumor cells in vitro. We observed that 10 microM of HMA could effectively increase the cell death by heating at 43 degrees in pH 6.6 medium but not in pH 7.5 medium. The B-3(+) at 50 microM alone had no effect on the thermosensitivity of cells, but it increased the thermosensitizing effect of HMA in acidic medium. Our results strongly suggested that a combination of HMA and B-3(+) may preferentially thermosensitize tumors in vivo since the interstitial environment in tumors is acidic relative to that in normal tissues.

Amiloride↗
PubMed1993

Radiation damage repair capacity of primary clonogenic blasts in acute lymphoblastic leukemia.

The sublethal radiation damage repair capacity of primary clonogenic blasts [i.e., leukemic progenitor cells (LPC)] from 74 newly diagnosed acute lymphoblastic leukemia (ALL) patients was analyzed using LPC colony assays. We determined the (a) Dq (quasithreshold dose) and n (extrapolation number) values from single dose radiation survival curves constructed according to the single-hit multitarget model of cell survival, (b) beta values and alpha:beta ratios from single dose radiation survival curves constructed according to the linear quadratic model of cell survival, and (c) recovery factor values from survival data in split-dose experiments. Clonogenic blasts from different ALL patients varied substantially in their ability to repair sublethal radiation damage. However, in 11 of 30 (37%) T-lineage ALL cases and 13 of 44 (30%) B-lineage ALL cases, the radiation survival curves of fresh LPC were characterized by a distinct initial shoulder, providing circumstantial evidence that LPC from a significant portion of ALL patients (24 of 74 cases = 32%) are able to repair sublethal radiation damage. Leukemic progenitor cells from 23 of 34 (68%) evaluable cases evaluated had alpha:beta ratios of < 5 Gy, indicating that they may possess a substantial capacity to repair sublethal radiation damage. In order to further elucidate the repair capacity of ALL LPC, we compared the antileukemic efficacy of fractionated irradiation with 2 x 2 Gy to the antileukemic efficacy of single-dose irradiation with 1 x 4 Gy. In 20 of 28 cases (71%), a > or = 20% increase in LPC survival (recovery factor > or = 1.2) was observed when 4 Gy were delivered in two doses instead of a single dose, providing direct evidence that ALL LPC are able to repair sublethal radiation damage. Our results indicate that modifications in total body irradiation regimens, currently administered prior to bone marrow transplantation, may be necessary to diminish the probability of relapse in high-risk ALL.

Adolescent↗
PubMed1993

Lack of CD24 antigen expression in B-lineage acute lymphoblastic leukemia is associated with intrinsic radiation resistance of primary clonogenic blasts.

The radiation sensitivity of primary clonogenic blasts from 27 children with immunologically classified CD2-CD5-CD7-CD19+slg- B-lineage acute lymphoblastic leukemia (ALL) was analyzed using leukemic progenitor cell (LPC) colony assays. Radiation survival curves of primary clonogenic blasts (ie, LPC) were constructed for each patient using computer programs for the single-hit multitarget as well as the linear quadratic models of cell survival. The D0 values ranged from 49 to 891 cGy (median, 239 cGy; mean +/- SE, 307 +/- 44 cGy) and the alpha values ranged from 0.000 to 2.047 Gy-1 (median, 0.156 Gy-1; mean +/- SE, 0.284 +/- 0.078 Gy-1). Patients were divided into groups according to sex, age, white blood cell count (WBC) at diagnosis, plating efficiency of primary bone marrow blasts, and immunophenotype. Patient sex, age, WBC at diagnosis, or in vitro plating efficiency was not associated with radiation resistance. Notably, freshly isolated primary clonogenic blasts from patients with a CD19+CD24-CD34+ composite immunophenotype (stage I B-cell precursor [BCP]) had 2.2-fold higher D0 values (P = .005) and 3.4-fold lower alpha values (P = .05) than those from patients with a CD19+CD24+CD34+ (stage II BCP) or CD19+CD24+CD34- (stage III BCP) immunophenotype. The relative values for CD24- primary clonogenic blasts signify greater intrinsic radiation resistance. Furthermore, the CD19+CD24-CD34+ immunophenotype had a larger radiation resistant fraction. Whereas only 60% of CD19+CD24+CD34+ and 33% of CD19+CD24+CD34- cases had clonogenic blasts with alpha < or = 0.2, 100% of CD19+CD24-CD34+ cases had clonogenic blasts with alpha < or = 0.2. Furthermore, clonogenic blasts from established CD19+CD24- B-lineage ALL cell lines were significantly more radiation resistant than CD19+CD24+ B-lineage ALL cell lines. Notably, radiation doses sufficient to induce apoptosis of CD24- B-lineage ALL cells were higher than those capable of inducing apoptosis in CD24+ B-lineage ALL cells. Thus, the lack of CD24 surface antigen expression in B-lineage ALL is associated with intrinsic radiation resistance at the level of primary clonogenic blasts.

Antigens, CD↗
PubMed1993

Antitumor effect of interleukin 1 alpha in combination with hyperthermia.

The combined effects of interleukin-1 alpha (IL-1 alpha) and hyperthermia on SCK tumors grown in the legs of A/J mice were investigated. When the host mice were given i.p. injections of 25 micrograms/kg IL-1 alpha, the tumor blood perfusion, as measured with the 86Rb uptake method, significantly declined, reaching minimum blood perfusion in 3-5 h. Although the tumor blood perfusion started to rise thereafter, the recovery was still incomplete 1 day later. Hyperthermia at 42.5 degrees C or 43.5 degrees C for 1 h also caused a marked decline in tumor blood perfusion. When the tumors were heated 5 h after an i.p. injection of IL-1 alpha at 25 micrograms/kg, at which time the tumor blood perfusion was low, the tumor blood perfusion decreased further. The heating of tumors at 42.5 degrees C or 43 degrees C for 1 h significantly reduced the clonogenic cell number in the tumors, delayed the tumor growth, and prolonged the survival time of host animals. The antitumor effect of 25 micrograms/kg IL-1 alpha alone, as judged from the clonogenic cell number, tumor growth delay, and host survival, was smaller than that of hyperthermia. When the host mice were treated with IL-1 alpha and the tumors were heated 5 h later, the decline in the clonogenic tumor cell number, tumor growth delay, and prolongation of host survival were significantly greater than those produced by either treatment alone. It was concluded that the prior reduction of blood perfusion by IL-1 alpha potentiated the antitumor effect of subsequent heatings.

Animals↗
PubMed1993

Tyrosine phosphorylation is a mandatory proximal step in radiation-induced activation of the protein kinase C signaling pathway in human B-lymphocyte precursors.

Ionizing radiation triggers a signal in human B-lymphocyte precursors that is intimately linked to an active protein-tyrosine kinase regulatory pathway. We show that in B-lymphocyte precursors, irradiation with gamma-rays leads to (i) stimulation of phosphatidylinositol turnover; (ii) downstream activation by covalent modification of multiple serine-specific protein kinases, including protein kinase C; and (iii) activation of nuclear factor kappa B. All of the radiation-induced signals were effectively prevented by the protein-tyrosine kinase inhibitors genistein and herbimycin A. Thus, tyrosine phosphorylation is an important and perhaps mandatory proximal step in the activation of the protein kinase C signaling cascade in human B-lymphocyte precursors. Our report expands current knowledge of the radiation-induced signaling cascade by clarifying the chronological sequence of biochemical events that follow irradiation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Endothelial cell growth factor (ECGF) application to irradiated soft tissue.

Delayed postoperative wound healing in previously radiated cancer patients is a common and debilitating occurrence. Prior studies have given evidence that endothelial cell growth factor (ECGF) can accelerate neovascularization in soft tissue. To explore its effects in irradiated tissue, an ECGF-heparin formulation (7200 micrograms/mL) contained in Gelfoam was applied to previously irradiated (N = 38) and nonirradiated skin flaps (N = 38) on rabbit ears. Both peripheral neovascularization and flap viability were quantitatively documented by polar planimetry and digital angiography in all flaps. The ECGF-heparin flaps had a greater than twofold increase in both vascularity and viability when compared to their controls among the irradiated and nonirradiated flaps (P < .01). Also, the additional viability and vascularization effects from ECGF-heparin did not appear statistically altered by previous radiation. These results support the promising angiogenic effect of ECGF-heparin in previously irradiated surgical wounds.

Animals↗
PubMed1993

Thermosensitization by lowering intracellular pH with 5-(N-ethyl-N-isopropyl) amiloride.

It has previously been reported that amiloride, a diuretic drug, sensitizes cells to hyperthermia by inhibiting the Na+/H+ exchange through the plasma membrane and thus decreasing the intracellular pH (pHi), particularly in a low extracellular pH (pHe) environment. In the present study, the efficacy of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), an analog of amiloride, to lower the pHi and sensitize tumor cells to hyperthermia was investigated. It was observed that 10 microM EIPA was as effective as 500 microM amiloride to lower the pHi and to increase the thermal sensitivity of SCK tumor cells in vitro. The fact that lowering the pHi and increasing thermal sensitivity of tumor cells by EIPA are more pronounced in acidic medium suggests that the acidic intratumor environment may be exploited to selectively increase the thermal damage in tumors relative to normal tissues by EIPA or its analogs.

Amiloride↗
PubMed1993

Enhancement of hyperthermia effect in vivo by amiloride and DIDS.

PURPOSE: Intracellular pH is regulated mainly by Na+/H+ antiport and Cl-/HCO3- exchange through the cell membrane. Amiloride (3,5-diamino-6-chloro-N-(diaminomethylene)pyrazine carboxamide) is a diuretic drug that blocks Na+/H+ antiport and DIDS (4,4-diisothiocyanatostilbene-2,2'-disulfonic acid) is an inhibitor of Cl-/HCO3- exchange. We investigated the potency of these drugs to lower pHi and increase the thermosensitivity of tumors in vivo. MATERIALS AND METHODS: The cytocidal effect of heat in combination with drug effect in vivo was studied using the in vivo-in vitro clonogenic assay method and the tumor growth delay method with SCK tumors, a mammary adenocarcinoma, on the hind limbs of A/J mice. The effects of amiloride and DIDS on tumor pHi and high energy phosphate levels were investigated using 31P-NMR. RESULTS: We observed that amiloride or DIDS alone increased the effect of hyperthermia at 42.5 degrees C or 43.5 degrees C to suppress tumor growth. The thermosensitization was greater when the two drugs were combined. For example, hyperthermia at 43.5 degrees C alone resulted in a tumor growth delay of about 4 days. When 10 mg/kg amiloride or 25 mg/kg DIDS was injected prior to heating, the growth delay increased to about 6 days. When both drugs were injected prior to heating, a total growth delay of 8 days was obtained. In vivo-in vitro excision assays for cell survival demonstrated that these drugs enhanced the heat-induced tumor cell death. An i.p. injection of 10 mg/kg amiloride plus 25 mg/kg DIDS did not lower the tumor pHi over a 120 min interval. Heating the tumors at 42.5 degrees C for 1 hr significantly lowered the pHi and when the tumor-bearing mice were injected i.p with amiloride and DIDS, and the tumors were heated 1 hr later, the drop in pHi was greater relative to that by heating alone. Heating alone significantly lowered the tumor energy levels as indicated by PCr/Pi and beta-ATP/Pi ratios and an i.p. injection of 25 mg/kg amiloride prior to heating further reduced the energy status in the tumors. CONCLUSION: Amiloride or its analogs and DIDS may be useful in increasing the therapeutic efficacy of hyperthermia treatments by enhancing the reduction in tumor pHi.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1993

Improved tumour oxygenation and radiosensitization by combination with nicotinamide and pentoxifylline.

We hypothesized that the combination of pentoxifylline (PTX) and nicotinamide (NA) can reduce the radioresistance of FSaII murine fibrosarcoma by improving oxygenation of the hypoxic tumour cells. The purpose of this study was to test the hypothesis; first, tumour blood flow after treatment with NA, PTX, and the combination (PTX+NA) was measured using laser Doppler flowmetry. Second, intratumour pO2 after various treatments was measured polarographically using O2 microelectrodes. Third, the radiation response was also measured, i.e. after an exposure to 20 Gy, the time required to reach a four-fold increase in initial tumour volume was 18 days in the saline-treated control group, 21 days in the NA-treated group, 26 days in the PTX-treated group, but was 36 days in PTX+NA treated group. Interestingly, tumour blood flow significantly increased at 10 min after injection of PTX+NA. The mean pO2 in untreated control tumours was 7.5 mmHg, increasing to 13.1 mmHg after 500 mg/kg of NA alone. Repeated injections of PTX with 100 mg/kg/day for 3 days significantly increased intratumour pO2 to 17.2 mmHg. Compared with PTX alone, PTX+NA slightly increased intratumour pO2 from 17.2 to 18.5 mmHg. However, the percentage of regions having values < 2.5 mmHg significantly decreased from 5% with PTX alone to 1% with PTX+NA. In conclusion, single or multiple injections of PTX may increase available O2 in the tumour and thus ameliorate hypoxia in tumour microregions. As previously reported, the subsequent injection of NA may efficiently oxygenate acutely hypoxic cells. Consequently, PTX+NA may increase the radioresponse of tumours by oxygenating chronic as well as acutely hypoxic cells. PTX alone or in combination with NA is potentially useful to radiosensitize tumours.

Animals↗
PubMed1993

The in vitro radiosensitization of human glioblastoma with pentoxifylline.

There is evidence that pentoxifylline may be both a radioprotector of normal tissue and a radiosensitizer of tumor cells. This article reviews this evidence and then describes our own laboratory study to determine whether pentoxifylline is a radiosensitizer of human glioblastoma cells in vitro. Human glioblastoma multiforme cells (SNB19 cell line) were irradiated in vitro with and without pentoxifylline. Regression of the log ratios (quotient of surviving colonies) revealed greater tumor cell kill in the PTX group, and the difference increased as the radiation dose increased (p < 0.01 at the 750 and 1000 cGY doses). Before the hypothesis that PTX is a radiosensitizer of hypoxic tumor cells can be confirmed or denied, it must be determined if the agent also has a separate mechanism of tumoricidal activity. Whereas in vivo models allow the well-documented rheologic, immunologic and oxygen-related effects of PTX to be active simultaneously, the in vitro model described herein excludes the effects of such systemic actions and focuses on mechanisms at the cellular or subcellular level. These data suggest there exists such a mechanism of tumoricidal activity of PTX that has not been previously identified.

Cell Survival↗
PubMed1993

Intrinsic radiation resistance of primary clonogenic blasts from children with newly diagnosed B-cell precursor acute lymphoblastic leukemia.

The radiation sensitivity of primary clonogenic blasts from 44 children with newly diagnosed B-cell precursor acute lymphoblastic leukemia (ALL) was analyzed using leukemic progenitor cell (LPC) colony assays. The derived values for SF2 (surviving fraction at 200 cGy) and alpha (initial slope of radiation survival curves constructed according to the linear quadratic model) indicated a marked interpatient heterogeneity in intrinsic radiation sensitivity of LPC populations. The SF2 values ranged from 0.01 to 1.00 (median = 0.430; mean +/- SE = 0.47 +/- 0.04), and the alpha values ranged from 0.000 to 3.272 Gy-1 (median = 0.280 Gy-1; mean +/- SE = 0.430 +/- 0.093 Gy-1). When CD19+ CD34+ versus CD19+ CD34- immunophenotypes were compared, a trend toward higher SF2 and lower alpha values were observed in LPC from CD34+ patients, consistent with greater radiation resistance. When patients were divided into three approximately equal groups based on increasing levels of CD34 expression, a clear ordering effect was observed indicating that increased CD34 expression levels are associated with significantly higher radiation resistance at the level of B-lineage LPC. The highest CD34 expression group (> or = 75% positivity) had 1.4-fold higher SF2 (P = 0.05) and twofold lower alpha values (P = 0.06) than the lowest group (< 30% positivity). Furthermore, the CD34 positivity of radiation resistant (alpha < or = 0.2 and SF2 > or = 0.5) B-cell precursor ALL cases was greater than the CD34 positivity of radiation sensitive (alpha > 0.2 and/or SF2 < 0.5) cases (56 +/- 9% versus 34 +/- 9%, P = 0.09). Whereas only 6 of 16 (38%) of radiation sensitive cases were CD34+, 11 of 15 (73%) of radiation resistant cases expressed CD34 (P = 0.04). Our results offer new insights into the inherent and/or acquired radiation resistance of primary clonogenic blasts from B-cell precursor ALL patients.

Age Factors↗
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↗