[Chronic myeloid leukemia: progress and prospects].
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Antineoplastic Agents↗
Biomedical subjects
D Russo
Publications and source records attributed to D Russo.
Effects of alpha-IFN on chronic myeloid leukemia (CML) hematopoiesis maintained in long-term cultures.
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Cell Adhesion↗
Extracellular domain chimeras of the TSH and LH/CG receptors reveal the mid-region (amino acids 171-260) to play a vital role in high affinity TSH binding.
We constructed a series of TSH-LH/CG receptor chimeras by homologous substitution of relatively small regions of the TSH receptor extracellular domain for the corresponding region of the extracellular domain of the LH/CG receptor. Constructs were stably expressed in Chinese hamster ovary cells. Of the five chimeric receptors, only TSH-LHR-14, which contains mid-region domain C (amino acid residues 171-260) of the extracellular component of the TSH receptor, exhibited TSH binding of relatively high affinity. Consistent with this TSH binding, chimera TSH-LHR-14 was the only one that demonstrated a functional response to TSH stimulation in terms of intracellular cAMP generation. These data indicate that domain C plays a vital role in TSH receptor function.
Amino Acid Sequence↗
Functional analysis of the cytoplasmic domains of the human thyrotropin receptor by site-directed mutagenesis.
The thyrotropin (TSH) receptor belongs to a family of guanine nucleotide protein-coupled receptors with seven transmembrane-spanning regions joined regulatory together by extracellular and intracellular loops. The cytoplasmic domain comprises three cytoplasmic loops and a cytoplasmic tail that are likely to be important in coupling of the receptor to the guanine nucleotide proteins. To address the question of which portions of the cytoplasmic domain of the TSH receptor are important in this process, we have altered groups of amino acids in the region of the TSH receptor by site-directed mutagenesis. Because of the low affinity of TSH binding to the TSH receptor mutated in the amino terminus of the second cytoplasmic loop and the amino terminus of the cytoplasmic tail, definitive conclusions cannot be made regarding the roles of these regions in signal transduction. However, our data indicate that the first cytoplasmic loop (residues 441-450), the carboxyl-terminal region of the second cytoplasmic loop (residues 528-537), and the carboxyl-terminal (but not the amino-terminal) region of the third cytoplasmic loop (residues 617-625) are important in the ability of the TSH receptor to mediate an increase in intracellular cAMP production. Furthermore, two-thirds of the carboxyl-terminal end of the cytoplasmic tail (residues 709-764; corresponding to the region not conserved between the TSH and lutropin/chorionic gonadotropin receptors) can be removed without functional impairment of the TSH receptor.
Amino Acid Sequence↗
An insertion in the human thyrotropin receptor critical for high affinity hormone binding.
Thyrotropin (TSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) are structurally related glycoprotein hormones, which bind to receptors that share a high degree of sequence similarity. However, comparison of the primary amino acid sequences of the TSH and LH-CG receptors reveals two unique insertions of 8 and 50 amino acids in the extracellular domain of the TSH receptor. The functional significance of these insertions were determined by site-directed mutagenesis. Deletion of the 50-amino acid tract (residues 317 to 366) had no effect on TSH binding or on TSH and thyroid-stimulating immunoglobulin (TSI) biological activities. In contrast, either deletion or substitution of the eight-amino acid region (residues 38 to 45) abolished these activities. This eight-amino acid tract near the amino terminus of the TSH receptor appears to be an important site of interaction for both TSH and TSI.
Animals↗
Sensitivity of chronic myeloid leukemia hemopoietic progenitors to PTT-119 in combination with human recombinant interferon alpha and gamma.
PTT-119, a new synthetic alkylating compound, has shown a marked "in vitro" inhibitory effect on chronic myeloid leukemia (CML) granulo-monocytic precursors (CFU-GM) at doses greater than 5 micrograms/ml. Based on previous experiences of synergistic associations between alkylating drugs and biological modifiers, we tested the effects of low doses of PTT-119 (from 0.1 to 1 microgram/ml) in concert with alpha, gamma, or alpha + gamma interferons and compared to IFNs alone, in order to investigate an alternative choice for treatment of CML patients in chronic phase. Our results showed a significantly higher CFU-GM cloning inhibition after addition of 100 or 1,000 U/ml of alpha IFN to 0.1 microgram/ml PTT-119 (from 39.6% +/- 26.6 SD to 80.7% +/- 10 SD and 91.5% +/- 8 SD, respectively), while gamma IFN resulted in only a slight increase in colony growth inhibition when compared to the drug used alone. The association of alpha plus gamma IFN coupled with PTT-119 treatment did not significantly improve the results observed after exposure of leukemic progenitors to PTT-119 and alpha IFN alone. We conclude that a combined treatment with PTT-119 and IFN is probably worth testing both for purging methods before autologous bone marrow transplantation and for in vivo administration in chronic myeloid leukemia.
Antineoplastic Agents↗
Effect of thyrotropin and cAMP on FRTL5 cell growth in a serum free medium.
TSH-induced proliferation of FRTL5 cells was studied in a chemically serum-free, defined medium. FRTL5 cells incubated for several days in a medium lacking of serum and hormones were fully able to respond to TSH in terms of cAMP production and iodine uptake. In the same medium, TSH stimulated FRTL5 cell growth as assessed by thymidine incorporation, DNA content and cell count. In these experimental conditions the cellular doubling time was of 7.5 days as compared to 40 h when calf serum was present together with TSH. Cholera toxin, forskolin and (bu)2cAMP, substances able to selectively increase intracellular cAMP levels, were not as efficient as TSH in inducing FRTL5 cell growth. However, both TSH and (bu)2cAMP, in a similar way, induced c-myc gene expression and cellular progression through the prereplicative phase of cell division. These data demonstrate that cAMP-dependent mechanisms are only partially responsible for TSH-induced FRTL5 cell growth, thus suggesting a role of cAMP-independent mechanisms.
Animals↗
Vascular hypertrophy, renin and blood pressure in the young spontaneously hypertensive rat.
1. Cardiovascular reactivity, blood vessel morphology, blood pressure and the activity of the renin-angiotensin system were determined in the 3-week-old spontaneously hypertensive (SHR), Wistar-Kyoto (WKY) and outbred Wistar (WIS) rat. 2. In an isolated perfused mesenteric artery preparation the SHR had a significantly increased maximum response to KCl and noradrenaline (P less than 0.02) compared with the WKY. Using a myograph, vascular structure was measured over a range of resistance arteries and showed a significant correlation between lumen diameter and both media cross-sectional area and thickness, with the regression line for the SHR shifted upwards indicating both increased media area and thickness. This was associated with a slight, but significant, narrowing of the lumen (P less than 0.01) and an increased media/lumen ratio (0.049 +/- 0.01, 0.034 +/- 0.007, 0.036 +/- 0.008 for SHR, WKY and WIS, respectively, means +/- SD P less than 0.001). The SHR had a greater heart/body weight ratio than either the WKY or the WIS (P less than 0.001). 3. Both mesenteric artery and membrane protein content were higher in the SHR, indicating an increase in cell size or number. 4. Plasma renin activity (means +/- SD) was lower in the SHR (1.0 +/- 0.7 pmol of angiotensin I h-1 ml-1) than in the WKY (2.2 +/- 1.2 pmol of angiotensin I h-1 ml-1, P less than 0.001) but not different from that in the WIS (1.2 +/- 0.8 pmol of angiotensin I h-1 ml-1). Mesenteric artery vascular renin concentration was also lower in the SHR (P = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Absence of acute nephrotoxicity with low doses of cyclosporin: experimental study in the rat.
No study has, to our knowledge, evaluated the acute effects of low immunosuppressive doses of cyclosporin (CsA) on renal function. To establish whether a relationship exists between the dosage of CsA and the onset of nephrotoxicity, 28 rats were studied by renal clearances before (control) and after i.v. administration of different doses of CsA: 3 mg/kg b.w. (group 1); 7 mg/kg b.w. (group 2); 11 mg/kg b.w. (group 3); 15 mg/kg b.w. (group 4). No change in renal function was observed between control and the post-CsA period in groups 1 and 2. GFR (inulin clearance) was decreased vs the control period in group 3 and group 4 (-22% and -37%, respectively, P less than 0.001); the difference between these two groups was statistically significant (P less than 0.01). Effective renal plasma flow (PAH clearance) was similarly decreased in groups 3 and 4 vs their control periods (-21% and -28%, respectively, P less than 0.001) due to the increase of total renal vascular resistance (+41% and +42%, respectively, P less than 0.001). Filtration fraction was significantly decreased by CsA in group 4 (P less than 0.01 vs the control period). PAH renal extraction, urinary volume, and sodium and potassium excretion were similar in all groups before and after CsA. PRA and ADH were significantly increased only in group 4 (P less than 0.01) vs the baseline values. A high and significant relationship was detected between CsA dosage and the decrease of GFR (r = 0.81, P less than 0.001) and RPF (r = 0.612, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Increased sensitivity to noradrenaline in glucocorticoid-treated rats: the effects of indomethacin and desipramine.
Vascular responsiveness was evaluated in perfused mesenteric arteries from rats infused with dexamethasone (2 micrograms/day). Full dose-response curves to noradrenaline, vasopressin and potassium chloride were established. In order to investigate whether prostaglandins or noradrenaline uptake were involved in dexamethasone-induced pressor changes, vascular responses were compared before and during treatment with either indomethacin (a cyclo-oxygenase inhibitor) or desipramine (an inhibitor of neuronal catecholamine uptake). Dexamethasone-treated tissues showed an increased vascular sensitivity to noradrenaline compared with controls; the maximal response was greater and the concentrations of agonist required for a 50% response (EC50) was less in dexamethasone-treated tissues. The responses to vasopressin and potassium chloride were not affected. Systolic blood pressure in dexamethasone-treated rats was not significantly different from that in controls. Indomethacin infusion decreased the vascular responsiveness to noradrenaline in control and dexamethasone-treated rats to a similar degree. Noradrenaline responses after indomethacin treatment were not significantly different in control and dexamethasone-treated tissues. 6-Keto-prostaglandin-F1 alpha output during stimulation with noradrenaline was not affected by dexamethasone. Desipramine lowered pressor responses to noradrenaline at all concentrations and decreased the maximal response in tissues from dexamethasone-treated but not control rats. However, during infusion with desipramine, the EC50 for noradrenaline after dexamethasone was still less than in controls. Dexamethasone at low doses appears to selectively increase vascular sensitivity to noradrenaline in rats at a prehypertensive stage by changing prostaglandin synthesis and, possibly, neuronal uptake of noradrenaline.
Animals↗
Torasemide, a new loop diuretic, in patients with chronic renal failure.
Torasemide, a new loop diuretic, was administered in 9 hospitalized patients with chronic renal failure to treat both arterial hypertension and peripheral edema. The urine of 5 patients was collected over 12-hour periods to assess the long-lasting diuretic activity of torasemide. Torasemide induced a significant decrease in blood pressure and reversion of peripheral edema in all patients without adverse effects. Torasemide is a high-ceiling loop diuretic, useful in correcting extracellular fluid volume expansion in patients with chronic renal failure.
Adult↗
Randomised prospective study on renal effects of two different contrast media in humans: protective role of a calcium channel blocker.
Contrast media affect renal hemodynamics. Hyperosmolality is regarded as the major factor responsible for renal hemodynamic changes. In this study, the role of osmolality was evaluated in 30 hospitalized patients without risk factors during intravenous pyelography. Contrast media with low and high osmolality were used. In addition, nifedipine was administered before infusion of high-osmolality contrast to evaluate the role of calcium ions in radiocontrast-induced changes of renal hemodynamics. Hyperosmolar contrast reduced renal plasma flow and glomerular filtration rate. Calcium channel blocker prevented changes of renal hemodynamics. Hyperosmolality appears the most likely factor affecting renal hemodynamics during hyperosmolar radiocontrast infusion. Calcium channel blocker may prevent renal changes due to hyperosmolar medium.
Adult↗
[Correlations between morphometric characteristics and the presence of lymph node metastasis in stage T1 and T2 breast carcinoma].
In this study the relationship between cyto-morphometric characteristics of breast cancer and lymph node status was investigated. The study was conducted on 20 cases of T1-T2 breast cancer with node metastasis and 20 cases of T1-T2 breast cancer without node metastasis. About 100 nuclei for each patient were analyzed by means of a computerized image analyzer, and mean nuclear diameter, mean nuclear area, mean form factor and number of cells in 8 classes of diameter were studied. Mean mitotic index was also calculated. No statistic difference was found for all these variables, between the two groups. In conclusion, cyto-morphometric parameters although often represent an index of aggressiveness, they are not related to lymph node status. This one is, in fact, only an indicator of tumor's ability to spread, and tumor's diffusion can occur through different ways from the lymphatic one.
Breast Neoplasms↗
[Impairment of diuresis in surgical intervention. Role of urinary prostaglandins].
In 8 patients who underwent abdominal surgery for non-neoplastic reasons, we have evaluated some parameters of renal function (PRP, NaU, GFR and diuresis) plasma levels of PRA and ADH and urinary prostaglandins PGE2 and 6-keto-PGF1 alpha. In 4 patients we found that surgery per se was associated with enhancements of PRA, ADH and 6-keto-PGF1 alpha. In other 4 patients, Indomethacin, a specific inhibitor of prostaglandin synthesis was given and this was followed by impairment of natriuresis and RPF. These data confirm the central role of prostaglandins in the control of diuresis and natriuresis and suggest that use of drugs affecting prostaglandin synthesis should be avoided in patients who are undergoing surgery.
Adult↗
Circling behavior: ethological analysis and functional considerations.
Head-turning and circling movements evoked by substantia nigra (pars compacta) (SNpc) stimulation have been ethologically analyzed in order to attribute a functional meaning to these lateralization processes. It has been shown that these motor acts, separated by a constant interval, may be considered a fixed action pattern. The duration of the single acts depends on the SNpc stimulation parameters: the increase in the stimulus strength produces an increase in the number of turns but does not induce the disappearance of the orientation movement. The body movement is always preceded by the head-movement. Haloperidol administration induces a dose-related increase of the orientation component of the motor pattern. These data together with others in the literature suggest the participation of the SNpc in the mechanism of shift in the focus of attention from one point to another in the contralateral surrounding environment.
Animals↗
The influence of dopaminergic A10 neurons on the motor pattern evoked by substantia nigra (pars compacta) stimulation.
The influence of the mesolimbic-mesocortical dopaminergic (DA) system on the motor pattern evoked by substantia nigra pars compacta (SNpc) stimulation was studied. Electrical stimulation of the A10 group of neurons caused an inhibitory effect preferentially directed towards the orientation movement. Sulpiride administration at low dosages (50 mg/kg i.p.) did not modify this movement at the basal condition, but abolished the increase of its duration induced by ventral tegmental area (VTA) co-stimulation. Mesolimbic activation opposes the effects of SNpc stimulation, restraining the animal in its antero-posterior axis by means of orientation movement inhibition. The results suggest a role of the DA mesolimbic-mesocortical system in the maintenance of focused attention.
Animals↗
Treatment of Ph+ chronic myeloid leukemia by gamma interferon.
The clinical, hematologic and cytogenetic effects of human recombinant gamma interferon (IFN) were investigated in 14 patients with Ph+ chronic myeloid leukemia (CML). Gamma-IFN was given at a daily dosage of 0.50 mg (= 10 x 10(6) U)/m2 from the 3rd week of treatment on, but the dosage had to be reduced to 0.25 mg/m2 in 10 cases and to 0.35 mg/m2 in 2 cases, because of the severity and persistence of side effects (mainly fever, fatigue, headache and pain). Only 2 patients tolerated the full dosage. The overall response rate was 64% (1 complete and 8 partial hematologic responses). Only patients in stable chronic phase responded. Two out of two patients in unstable chronic phase and two out of two patients in accelerated phase failed to respond. Eight out of nine responding patients remained in remission throughout the duration of treatment (30 to 35 weeks). No karyotypic conversion was detected. These data show that gamma IFN alone is effective in Ph+ CML, but that side effects can limit substantially the dosage and duration of treatment.
Adult↗
Radiation sensitivity of human lung cancer cell lines.
X-Ray survival curves were determined using a panel of 17 human lung cancer cell lines, with emphasis on non-small cell lung cancer (NSCLC). In contrast to classic small cell lung cancer (SCLC) cell lines, NSCLC cell lines were generally less sensitive to radiation as evidenced by higher radiation survival curve extrapolation numbers, surviving fraction values following a 2 Gy dose (SF2) and the mean inactivation dose values (D) values. The spectrum of in vitro radiation responses observed was similar to that expected in clinical practice, although mesothelioma was unexpectedly sensitive in vitro. Differences in radiosensitivity were best distinguished by comparison of SF2 values. Some NSCLC lines were relatively sensitive, and in view of this demonstrable variability in radiation sensitivity, the SF2 value may be useful for in vitro predictive assay testing of clinical specimens.
Adenocarcinoma↗