Biomedical subjects
Publications and source records attributed to C Rose.
A case of locally advanced basal cell carcinoma of the head treated with systemic chemotherapy consisting of cis-platinum, fluorouracil and bleomycin is reported. The treatment resulted in complete remission lasting for 13 months.
Endogenous cholecystokinin immunoreactivity released by depolarization of slices of rat cerebral cortex undergoes extensive degradation (85% of released immunoreactivity) before reaching the incubation medium. In order to identify the responsible peptidases, a large number of inhibitors of the four catalytic classes were tested for their protective effects. Inhibitors of metallopeptidases (bestatin, amastatin, puromycin, Thiorphan, captopril, o-phenantroline), thiol-peptidases, (leupeptin, antipain, p-hydroxymercuribenzoate) or carboxyl-peptidases (pepstatin) had generally low if any protective effect. By contrast, several serine peptidase inhibitors, i.e. diisopropyl-fluorophosphate, phenylmethylsulphonylfluoride or the chloromethylketone Ala-Ala-Pro-Val-CH2Cl, doubled the recovery of cholecystokinin immunoreactivity and the effect was amplified in the co-presence of bestatin, an aminopeptidase inhibitor and/or Thiorphan, an enkephalinase inhibitor. High-performance liquid chromatographic analysis of the cholecystokinin immunoreactivity recovered in medium in the absence of any inhibitor showed cholecystokinin-8 to be the major peak, representing 8% of the released immunoreactive material. Non-sulphated cholecystokinin-8 represented less than 1%, indicating that desulphation does not constitute a major inactivation pathway for the endogenous octapeptide. Cholecystokinin-5 was the major clearly identifiable immunoreactive fragment, representing 9% of released immunoreactivity in the absence of inhibitors. Its formation was decreased by about 50% in the presence of either diisopropyl-fluorophosphate or bestatin and Thiorphan and abolished when they were associated, suggesting that it resulted from the actions of a serine peptidase(s) and an aminopeptidase(s). Cholecystokinin-6 (or cholecystokinin-7) was less abundant, representing 4% of the released immunoreactivity, and its level was augmented in the presence of diisopropyl-fluorophosphate. Hence a serine endopeptidase cleaving the Met3-Gly4 bond of cholecystokinin-8 may represent a major inactivating peptidase for the endogenous neuropeptide. Additional metabolic pathways not blocked by serine peptidase inhibitors and resulting in the formation of cholecystokinin-6 (or cholecystokinin-7) and, possibly, cholecystokinin-4, are also suggested by the present approach.
The participation of a serine endopeptidase, previously shown to be involved in endogenous cholecystokinin inactivation [Rose, Camus and Schwartz (1989) Neuroscience 29, 583-594], in the hydrolysis of various exogenous cholecystokinin peptides was studied with slices from rat cerebral cortex. In order to protect intermediate fragments from further degradation and mimick experimental conditions in this previous study, most experiments were performed in the presence of Thiorphan, an enkephalinase inhibitor, and bestatin, an aminopeptidase inhibitor, which did not significantly affect the rate of cholecystokinin-8 hydrolysis. All peptide fragments formed after incubation of cholecystokinin-8, non-sulphated cholecystokinin-8, cholecystokinin-6, cholecystokinin-5, cholecystokinin-4 or Asp-Tyr-Met-Gly-Trp were identified by isocratic high-performance liquid chromatography in several systems, fluorescence spectra and/or amino acid analysis. When identified, the appearing fragments were quantified by u.v. spectrophotometry and found to fully account for the substrate disappearance. The hydrolysis rate was higher for short cholecystokinin peptides than for the octapeptide and was, in all cases, diminished by 30-50% in the presence of diisopropyl fluorophosphate, a serine peptidase inhibitor. One of the main hydrolysis products of cholecystokinin-8, or its non-sulphated analogue, was cholecystokinin-5, whose formation was impaired in the presence of diisopropyl fluorophosphate. Cholecystokinin-5 itself was apparently a substrate for a serine peptidase leading to the formation of the tripeptide Gly-Trp-Met, later cleaved into Trp-Met and Trp. Hence a serine endopeptidase(s) appears to be responsible for cleavage of the two peptides bonds of the cholecystokinin-8 molecule where the carboxyl group is donated by a methionine residue.2+n addition,
Fluosol-DA 20% (Fluosol) is an emulsion of perfluorodecalin and perfluorotripropylamine, which has the ability to carry oxygen and has been shown to enhance the ability of radiation to control tumors in animal studies. Since November 1984, patients with unresectable squamous cell carcinomas of the head and neck have been enrolled in a study to evaluate the safety and potential efficacy of this adjuvant therapy. Forty-six patients were entered of which 37 completed radiation and are evaluable. Patients were infused weekly with Fluosol and then breathed 100% oxygen for a minimum of 30 minutes prior to and during radiation. Eleven patients received 5 infusions of 8 mL/Kg, four patients 6 infusions of 8 mL/Kg, five patients 5 infusions of 9 mL/Kg, seven patients 7 infusions of 7 mL/Kg and eight patients 8 infusions of 7 mL/Kg. Nine patients had Stage III disease, 20 patients Stage IV disease and 8 patients had failed previous therapy with chemotherapy and/or surgery. The radiation doses delivered ranged from 6600 cGy to 7500 cGy. The overall complete response rate for this group was 76%. All 9 Stage III patients were complete responders, 13 of 20 Stage IV responded and 6 of 8 with previous therapy were complete responders. The survival rate at 1 year was 67% for absolute and 78% as determinant. Of those patients achieving a complete response, 75% continued free of disease 1 year after therapy. Out of 254 total test doses, 11 patients experienced a reaction to the test dose of Fluosol. Of 235 total infusions 6 patients experienced a reaction during the Fluosol infusion with 7 patients experiencing post infusion reactions. These were readily controlled with diphenhydramine or acetominophen. Elevated liver enzymes were observed in some patients with a mean time to normalization of 102 days for alkaline phosphatase, 39 days for SGOT, and 46 days for SGPT.
Norepinephrine handling by the dog liver was appraised by carrying out tracer-transient, multiple-indicator-dilution studies within steady-state conditions in a basal situation, during norepinephrine infusion and after the uptake inhibitor desipramine. In controls, tracer norepinephrine extraction averaged 61%, whereas bulk norepinephrine extraction was approximately 31%; intrahepatic secretion of unlabeled norepinephrine accounted for the difference. Infusion of norepinephrine, raising arterial levels more than an order of magnitude, constricted the hepatic vascular space but did not change tracer extraction; norepinephrine secretion remained essentially unchanged, and with this, bulk extraction approached tracer extraction. A theoretical analysis of norepinephrine uptake was developed. Analysis of tracer data with this indicated that the permeability surface products for influx and efflux, expressed per gram liver, did not change. Desipramine did not affect the uptake kinetics, indicating that the uptake process was virtually completely nonneurogenic. Late efflux of tracer normetanephrine product was detected but was small prior to recirculation. The study demonstrates that norepinephrine secretion ordinarily coexists with uptake and provides an approach to quantitating both.
Recent research has produced several new options for endocrine treatment of advanced breast cancer. Since one of the most intriguing characteristics of endocrine therapy is that new remissions are possible when subsequent endocrine modalities are used, it is important to evaluate their optimal sequence. Tamoxifen has become the most commonly used endocrine therapy for advanced breast cancer due to its few side effects and an overall response rate of 35%. Crossover data from randomised trials, comparing tamoxifen with either ablative, additive or inhibitive treatment, indicate that the highest overall response rate is obtained when tamoxifen is used as first-line endocrine therapy. Furthermore, it seems that oophorectomy in premenopausal, and aminoglutethimide or progestins in postmenopausal patients, are equally effective as second-line endocrine therapy. Despite an obvious clinical rationale for combined endocrine therapy, most trials have failed to show any benefit. Although data from trials combining tamoxifen with prednisolone or androgens seem promising, the use of combined endocrine therapy still has to be considered experimental.
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An LHRH agonist, Zoladex, was employed as a monthly depot in 56 previously untreated patients with advanced carcinoma of the prostate. Of 53 evaluable patients, 27 achieved partial remission and 7 were stable. Median duration of response was 10 months. A favorable subjective response was attained in 68% of the patients. During treatment, serum testosterone was in the castrate range in all patients except five. Possible explanations for this escape phenomenon are discussed. No toxicity was observed and treatment was well tolerated in all patients. Thirty-two patients underwent bilateral orchiectomy following treatment failure of Zoladex. In one patient partial remission according to protocol criteria was recorded. Treatment with LHRH agonists seems safe and may serve as an alternative to conventional hormonal treatment of advanced carcinoma of the prostate.
The prognosis and pattern of spread were related to body size and menopausal status in 863 patients with recurrent breast cancer. These patients were all enrolled in the adjuvant protocols of the Danish Breast Cancer Cooperative Group. The pattern of spread was illustrated by the number of metastases, the anatomical location of recurrence, and the rate of progression. Body size was estimated as height, weight, Quetelet index (QI), and body surface area (BSA). The body size was unassociated with both recurrence-free interval (RFI) and survival after recurrence (SAR). The groups of patients with different body size had both the same number and the same location of metastases. The tumour growth rates were estimated as clinical rates of progression (i.e. the time elapsed from a single distant metastasis until dissemination). The progression rate was unaffected by body size. Postmenopausal patients had a significantly shorter RFI and SAR compared to premenopausal patients. The number of metastatic sites, the anatomical location of metastases, and the rate of progression were similar in pre- and postmenopausal patients. The study could not confirm most findings from the literature which report a poor prognosis for patients with large body size. Moreover, the results do not suggest interactions between body size, menopausal status, and the clinical course of recurrent breast cancer.
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A new immunocytochemical assay for progesterone receptor (PgR-ICA) employing the monoclonal antibody JZB 39 was used to study tumors from two series of patients with breast cancer. In Series 1 assay results were in agreement with those of biochemistry in 76% of 338 cases (P less than 0.001) and in 54% of 101 cases in Series 2 (P less than 0.001). Agreement was better in Series 1 because it included fresher, previously untouched specimens. There were 70 patients in Series 1 with known clinical endocrine response. A negative assay correlated with disease progression in 45 of 57 patients, significantly better than with biochemistry (P = 0.013). In comparing 39 women with rapid disease progression with 39 free of disease at 5.1 years, those with PgR-ICA-positive tumors were over four times more likely to remain disease-free than those with negative results (P = 0.007). Product moment life-table analysis of 79 patients from Series 2 showed a significantly better cumulative survival for those with PgR-ICA-positive tumors (P = 0.047). These findings indicate that PgR-ICA should be of value in planning therapy and predicting disease course in breast cancer patients.
Lymphocytes from lymph nodes obtained from breast cancer patients undergoing mastectomy were fused with the 0467.3, UC729HF2, or KR-12 human cell lines, totaling 42 fusions with lymphocytes from 23 patients. A total of 1696 human-human hybridomas were generated, 675 (39.8%) of which produced human IgG and/or IgM. Seventy-three human hybridomas produced antibodies binding to autologous malignant breast tissue and/or MCF-7 cells, as assayed by immunohistology or by cell-binding enzyme-linked immunosorbent assay. Twelve of these hybridomas, all reacting with malignant breast tissue, were subcloned to stabilize the production of human immunoglobulin. The reaction patterns of these 12 human monoclonal antibodies were investigated further by immunohistology on formalin-fixed, paraffin-embedded tissues. The reaction patterns of the various antibodies showed substantial variation and the antibodies reacted with a varying frequency with antigens expressed by different malignant breast tumors. One of these antibodies, MAC 40/43 (IgM), reacted with malignant breast and colon carcinomas and other epithelial derived neoplasms but did not react with normal breast tissue or with other normal and malignant tissues tested, except for a weak reaction with certain normal epithelial tissues. The antigen defined by MAC 40/43 was identified as a Mr approximately equal to 47,000 glycoprotein.
The hydrated volumes, Vh, of collagens extracted from various fish species were calculated by using the Simha-Einstein equation, and it was found that the hydration of warm-water fish collagen is greater than that of cold-water fish collagen (halibut). Although the intrinsic viscosities of warm-water fish (bigeye-tuna, carp and catfish) collagens are almost the same, the hydrated volume of bigeye-tuna collagen is approx. 1.5 and 3 times those of carp and catfish collagens respectively. The extent of hydration at 20 degrees C is in the following order: bigeye tuna greater than carp greater than catfish greater than halibut. The various thermodynamic activation parameters (delta G*, delta H* and delta S*) were calculated and it was found that they are useful for determining the exact denaturation temperature. It was calculated that the denaturation temperatures of halibut, bigeye-tuna, carp and catfish collagens are 17, 31, 32 and 26-30 degrees C respectively. The variations of hydration, intrinsic viscosity, denaturation temperature and the thermodynamic parameters with the variation of concentration of catfish collagen were also thoroughly examined. The change of thermodynamic parameters from coiled-coil to random-coil conformation upon denaturation of collagen were calculated from the amount of proline and hydroxyproline residues and compared with viscometric results.
The subclass of beta-adrenergic receptors mediating glycogenolysis in slices from cerebral cortex of the mouse, incubated in the presence of [3H]glucose, was identified by comparing the relative potencies of agonists and the inhibition constants of antagonists to those found on reference systems. (+/-)Isoprenaline, (-)adrenaline and (-)noradrenaline produced a concentration-related glycogenolysis with Kact values of 2.2 x 10(-8) M, 2.8 x 10(-7) M and 3.6 x 10(-7) M, respectively. Zinterol, a selective beta 2-adrenergic agonist, did not produce any glycogenolytic response even in a large concentration. Salbutamol, a predominantly beta 2-adrenergic receptor agonist, elicited in a very large concentration (10(-4) M) less than 40% glycogenolysis, an effect which was not related to stimulation of beta-adrenergic receptors. The predominantly beta 1-adrenergic receptor antagonists, practolol and metoprolol shifted the concentration-response curve to noradrenaline to the right, with apparent Ki values of 8.0 x 10(-7) M and 7.6 x 10(-8) M, respectively, close to those reported in the rat heart. These various data indicate that the glycogenolytic response is selectively mediated by beta 1-adrenergic receptors. Under experimental conditions which were strictly identical to those used to measure glycogenolysis, a saturable binding of [3H]dihydroalprenolol to the slices occurred with Kd and Bmax values consistent with corresponding values on cell free preparations. Whereas the Ki values of antagonists were similar on the two systems, the Kact values of agonists on glycogenolysis were 10 times less than the Ki values for the binding of [3H]dihydroalprenolol. This suggests that the maximal glycogenolytic response is elicited for a partial receptor occupancy.
Sera from foetal calves, newborn calves, athymic mice, and healthy postmenopausal women exert a growth inhibitory effect on the oestrogen receptor positive human breast cancer cell line MCF-7. This inhibitory effect of serum can be abrogated by oestradiol. Serum samples from 22 breast cancer patients were analysed for the amount of inhibitory activity in order to clarify whether regulation of cell proliferation of human breast cancer may occur via a modulation of the inhibitory activity in the patient's serum. Twenty of the 22 serum samples showed inhibitory activity and no difference was found in the degree of inhibition. These results do not support the hypothesis that breast cancer cells grow in vivo solely as a function of a reduced level of a serum-borne inhibitory activity; other mechanisms must be involved in the regulation of growth. We have found that MCF-7 cells, the growth of which is inhibited by serum from breast cancer patients, exhibit a reduced synthesis of three secreted proteins, and an increased amount of one protein, a 46K protein. Oestradiol induced cell proliferation is concomitant with stimulation of the synthesis of these three proteins and inhibition of the 46K protein. Regulation of growth of breast cancer may therefore occur via changes in the synthesis of secreted proteins, which exert a regulatory function on cell proliferation.
The question of whether the dissociation constant (Kd) observed for the binding between estradiol and the [3H]estrogen receptor (ER) indicates the existence of a single class of estrogen binding proteins in breast cancer tissue has been examined among a population of 3020 ER-positive (greater than or equal to 10 fmol/mg cytosol protein) primary breast cancer patients. The median value for Kds was found to be 0.9 X 10(-10) M. Kd values were only weakly correlated to ER concentrations in the respective biopsies. Nevertheless, high Kd values were associated with lower measured ER concentrations among pre/perimenopausal patients. Meanwhile, the frequencies of PgR-positivity are consistently high among pre/perimenopausal patients irrespective of Kd value. In contrast, the frequency of PgR-positivity is significantly lower among postmenopausal patients with high Kd values. Furthermore, postmenopausal patients with high Kd values (greater than 1.4 X 10(-10) M) tend to have shorter recurrence-free survivals than other ER-positive patients. A possible interpretation of these findings is that high Kd values reflect physiologically normal, cyclically high endogenous concentrations of estradiol in tumor tissue among pre/perimenopausal patients. Among the postmenopausal patients, the presence of high Kd values might reflect the presence of an estradiol binding molecule(s) slightly different from normal ER in the tissue of postmenopausal patients.