Relationship between a novel human cytotoxin (factor 2) produced by a B cell line (Karpas 160) and phorbol-myristate-acetate-associated cytotoxicity.

We found that 160b cells, a subclone of Karpas 160 human B cell line, spontaneously secreted a novel cytotoxin, factor 2 (F2). F2 was also extracted from the cells by 60% ammonium sulphate, 0.5% CHAPS and 0.28% Triton X-114. We were able to show that phorbol myristate acetate (PMA) greatly enhanced the production of F2, and PMA may also account for part of the putative F2 cytotoxic activity to K562 cells in crude preparations. We compared the cytotoxic effect of F2 with PMA-associated F2-like cytotoxicity to K562 cells as well as the adequacy of our schemes to purified F2 with regard to its separation from PMA. We found that it was possible to separate PMA from F2 preparations by gel filtration and Rotofor preparative isoelectric focusing. The fate of PMA was also monitored with 3H-PMA and chromatographic profiles of 3H-PMA were studied using DE52 and gel filtration chromatography. We were able to establish that less than 2.9% of the cytotoxicity to K562 was due to PMA. We also found that the radioactive peaks and cytotoxicity peaks to K562 were not well correlated, indicating that the cytotoxicity was not mainly due to remaining PMA. Activated charcoal removed virtually all F2 and PMA but not tumour necrosis factor activity. Our results also showed that cytotoxicity to K562 resulting from F2 or PMA-associated proteins had different physicochemical properties, indicating that they are different molecular entities. These findings are consistent with the earlier observation that 160 cells produce F2 spontaneously and that PMA can amplify its production significantly.     

Cyclical use of tamoxifen and high-dose medroxyprogesterone acetate in advanced estrogen receptor positive breast cancer

Summary One-hundred and seventy patients with estrogen receptor positive (10 pmol/g protein) advanced breast cancer have been treated in a prospective randomized study either with continuous tamoxifen 30 mg × 1 daily (TAM), or with TAM 30 mg × 1 daily for 8 weeks alternating with medroxyprogesterone acetate 500 mg × 2 daily for 8 weeks (TAM/HD-MPA). The response rate was 62% in the group treated with cyclic TAM/HD-MPA versus 41% in the TAM alone group (p = 0.02). There was no significant difference in duration of remissions or survival.     

The role of protein kinase C and its effect on GHRH in the regulation of hormone secretion by somatotrophinomas

In recent years, the most exciting advance inthe research of human pitllitary tumors is the discovery that 30 %--40 % of hfuman pituitary somatotrophinomas carry somatic missense single--basemutations within codons 201 and 227 of the genefor the a--subunit of the stimulatory GTP--bindingprotein, Gs (Gsa). These mutations, termed gsponcogenes, result in constitutive activity of adenylyl cyclase and the subsequent elevations in intracellular cAMP levels are thought to be responsiblefor tumor g…     

A combination therapy with mitomycin c, etoposide, doxifluridine and medroxyprogesterone acetate as second line therapy for advanced breast cancer refractory to combination chemotherapy of cyclophosphamide, doxorubicin and 5 fluorouracil

Thirty-two patients with advanced breast cancer refractory to combination chemotherapy with cyclophosphamide (CPA), doxorubicin (ADR) and 5-fluorouracil (5-FU) (CAF) were treated with the combination of mitomycin C, etoposide, doxifluridine and medroxyprogesterone acetate as second line therapy. Observed responses included 6 patients (18.7%) with complete response (CR) and 7 (21.9%) with partial response (PR). Two (50%) out of 4 patients who had bone pain due to bone metastasis noted pain relief. CR or PR were obtained in 4 out of 12 patients who had not responded to the previous CAF therapy. While grade III myelosuppression was observed in 3 patients, other adverse effects were minimal. It is suggested that this combination therapy may be recommended for advanced breast cancer patients as a second therapy.     

Experimental study and clinical use of poly(vinyl acetate) emulsion as liquid embolisation material

A new material, an emulsion of poly(vinyl acetate) was experimentally developed and clinically used to overcome several disadvantages in currently used liquid embolisation materials. The emulsion microparticles, 0.3–0.7 m in size, possessed cationic charge on the surface and hence aggregated immediately on contact with fluids containing anions. This inert polymer has the advantage that it does not induce a deleterious reaction in living tissue. Moreover, its medium is water and it is not adhesive, like the cyanoacrylates. Several concentrations of emulsion were injected into the renal arteries of dogs. For the investigation of tissue reactions and the possibility of recanalisation, the emulsion was injected into rats both subcutaneously and into the renal arteries. The renal artery injections in dogs showed adequate radiopacity and consistent complete occlusion. The lower the concentration of the emulsion, the smaller the arteries which could be occluded. Even at very low concentrations, however, venous occlusion did not occur. Histological study of the embolised rat kidney revealed no detectable damage in the vessel wall and no recanalisation for up to 6 months. The subcutaneously injected PVAc emulsion elicited mononuclear cell infiltration and gradual centripetal fibrosis, without any deleterious effect on the surrounding tissue. A cerebral arteriovenous malformation (AVM) was embolised using the material. Histology of the resected nidus showed findings similar to those in the animal experiments.     

Comparison between nafarelin acetate andd-Trp6-LHRH for temporary pituitary suppression in in vitro fertilization (IVF) patients: A prospective crossover study

Purpose Nafarelin acetate is a new gonadotropin releasing (GnRH) agonist analogue with unique potency, intranasal administration, and convenient storage. Hence, nafarelin was considered as an alternative for temporary pituitary suppression in patients undergoing ovulation induction in IVF. A crossover treatment in a prospective study was performed including 40 women with bilateral obstructed tubes and normal ovarian function, treated in 80 ovulation induction cycles using the long protocol. Twenty patients used nafarelin acetate 600 g/daily in their first cycle and received d-Trp6-LHRH, 0.5 mg/daily, in their following cycle. The other 20 women used decapeptyl in their first cycle and received nafarelin in the second.Results Estradiol suppression was achieved by both d-Trp6-LHRH and nafarelin at equal time intervals. The average total number of ampoules (P=0.0005) and the length of administration of hMG required for ovarian stimulation (P=0.0002) and the time interval between GnRHa initiation to oocyte retrieval (P=0.04) was significantly lower in nafarelin cycles. The number and the distribution between large and small follicles as well as the average number of oocytes retrieved did not differ between the two GnRH analogues.Conclusion Our results demonstrate that nafarelin acetate is comparable to d-Trp6-LHRH for temporary pituitary suppression used for controlled ovarian stimulation in IVF patients. However, using nafarelin ovarian stimulation was achieved with fewer ampoules of hMG, administered for a shorter period of time, thus with a lesser cost.     

Pharmacokinetic evaluation of two different formulations of megestrol acetate in patients with advanced malignancies

The bioequivalence of two megestrol acetate formulations, 160-mg tablets and 160-mg sachets, was investigated in a single-dose, open-label, balanced-for-sequence cross-over study involving 12 advanced-cancer patients. The observed plasma megestrol-acetate time course obtained with both formulations was consistent with the literature data. The main source of variability in the pharmacokinetic parameters was intersubject variability; drug formulation played only a minor (and nonsignificant) role. The width of the 90% confidence interval of the areaunder-the-curve (AUC) ratio (sachets: tablets) computed according to Schuirmann (0.9–1.4) was mainly due to the presence of a single outlier, showing an AUC ratio of 2.7. The trend to higher bioavailability of the new formulation was not significant, especially as compared with the doseresponse data reported in the literature.     

醋酸纤维膜电泳筛查血清铜蓝蛋白

目的：建立一种快速、有效的血清铜蓝蛋白（ＣＰ）筛查方法。方法：醋酸纤维膜电泳分离血清ＣＰ,盐酸联苯胺显示法。结果：用此方法可明确检测出Ｗｉｌｓｏｎ氏病患者血清中ＣＰ含量的变化。结论：醋酸纤维膜电泳检测血清ＣＰ是一种有效的血清ＣＰ筛查方法。     

The effects of cyclosporin A,tamoxifen, and medroxyprogesterone acetate on the enhancement of Adriamycin cytotoxicity in primary cultures of human breast epithelial cells

Summary Adriamycin (Adr), the single most active agent used in the treatment of breast cancer, may become ineffective as treatment progresses due to the development of multidrug resistant (MDR) tumors. A major mechanism associated with MDR is increased P-glycoprotein (Pgp) expression. This study examined the abilities of the anti-estrogen tamoxifen (TAM) and the progestin medroxyprogesterone acetate (MPA) as well as cyclosporin A (CsA), a known resistance modifier, to enhance the cytotoxic effects of Adr on human breast epithelial cells (HBEC) in primary culture. Pgp and estrogen receptor (ER) expression were determined in each of the cultures by immunocytochemical assays using the monoclonal antibodies C219 and H222 Sp, respectively. The Adr-sensitive, Pgp-, ER+ MCF-7 cell line and the Adr-resistant, Pgp+, ER-MCF7-AdrR cell line were used as controls. Primary cultures were categorized as HBEC from tissues with or without previous chemotherapy. Pgp was detected in 1 of the 15 cell cultures from tissues without previous chemotherapy and in 5 of the 6 cell cultures from tissues previously exposed to chemotherapy. Incubation with either CsA or MPA plus Adr enhanced Adr toxicity in Pgp+ but not Pgp- cell cultures, whereas TAM had no effect on the sensitivity of any of the cultures. Of the 21 primary cultures of HBEC, 3 were ER+. There was no correlation between the enhancement of Adr cytotoxicity and ER status. The data suggest that MPA as well as CsA may be useful as modifying agents in overcoming Pgp-associated multidrug resistance.     

Effects of lead,copper, and zinc on the rat's lactate dehydrogenase in vivo and in vitro

Following subacute intoxication of rats with Pb-, Cu-, and Zn-salts (separately or in mixture) for 5 weeks, the chelating agent D-penicillamine was administered for 3 weeks. In the course of the 3-month experiment, lactate dehydrogenase (LDH) was estimated in serum and in cytoplasmic fraction of the kidney. Pb²⁺ treatment resulted in an increase of LDH activity, Cu²⁺ in a slight decrease, whereas Zn²⁺ had no effect, respectively. Mixture of these metals caused a significant rise in the enzymatic activity. Seven weeks after the stoppage of the administration of toxic substances, altered LDH activity, both in serum and in kidney returned to normal. D-penicillamine treatment was found to accelerate a restoration of the enzyme activity.In the experiments in vitro, Cu²⁺ inhibited significantly the kidney LDH activity, Pb²⁺ and Zn²⁺ being 100- and 400-times less efficient, respectively. Cu²⁺ inhibition was reversed by D-penicillamine, whereas inhibition of LDH by Zn²⁺ or Pb²⁺ was irreversible.