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H R Chang

Publications and source records attributed to H R Chang.

At least 73 records · Page 4Linked to original sources
PubMed1989

In-vitro toxoplasmacidal activity of cationic electron carriers.

Exposing murine macrophages infected with the protozoan parasite Toxoplasma gondii to micromolar concentrations of some cationic electron carriers (dyes), resulted in complete killing of the intracellular parasites at concentrations at which these compounds did not seem toxic for the macrophages. The 50% inhibitory concentrations (with 95% confidence limits) were calculated as 0.26 (0.18-0.37), 1.35 (1-2.25), 0.45 (0.13-1.50), and 1.52 (0.91-2.53) microM for crystal violet, phenazine methosulphate, methylene blue and brilliant cresyl blue, respectively. The effects of these electron carriers did not appear to be the result of an enhancement of the natural antitoxoplasmic activity of the macrophages. None of the tested compounds was active against extracellular Tox. gondii as measured by ability to reinfect murine macrophages; thus, these dyes seem to act primarily on actively metabolizing, intracellular, Tox. gondii. Our data also suggest that the killing effect of the electron carriers was not related to the generation of reactive oxygen intermediates as judged by the inability of scavengers of these intermediates to block the activity against intracellular Tox. gondii. Further studies with related redox compounds would have an interesting chemotherapeutic perspective for treating toxoplasma infections.

Animals↗
PubMed1989

Somatic mosaicism for DNA repair capacity in fibroblasts derived from a group A xeroderma pigmentosum patient.

A female Japanese xeroderma pigmentosum (XP) patient with severe skin lesions and various neurologic abnormalities was assigned to complementation group A by conventional cell fusion studies. Ultraviolet (UV)-irradiated skin fibroblasts showed a biphasic survival curve, as measured by colony-forming ability. The surviving fraction decreased rapidly up to 2 J/m2 of UV, with a steep slope of D(O) (mean lethal dose) = 0.95 J/m2. At much higher doses it decreased more slowly, with D(O) = 3.5 J/m2. To èlucidate the cause of this unique survival response, we isolated a large number of independent clones from single colonies and measured their responses to UV. Of 81 clones analyzed, ten showed a marked resistance to killing by UV, which was only slightly more sensitive than normal cells, and these clones had a rate of unscheduled DNA synthesis (UDS) that was about 45% of normal cells. By contrast, the remaining 71 clones were extremely sensitive to UV, typical of XP group A strains, and had a UDS level 1%-3% of normals. Analysis of restriction fragment length polymorphism using seven polymorphic DNA probes indicated that the UV-resistant clones were derived from the same individual as the UV-sensitive clones. These results clearly demonstrate that this patient's fibroblast cells consist of two types with differing responses to UV, and provide direct evidence of somatic mosaicism for DNA repair capacity in an XP patient.

Cell Survival↗
PubMed1989

In vitro effects of three new 1,2,4-trioxanes (pentatroxane, thiahexatroxane, and hexatroxanone) on Toxoplasma gondii.

The in vitro effects of three synthetic, cis-fused, bicyclic 1,2,4-trioxanes (pentatroxane, thiahexatroxane, and hexatroxanone) against intracellular Toxoplasma gondii were studied. Unactivated peritoneal macrophages were infected with the virulent RH strain of T. gondii and exposed to the 1,2,4-trioxanes at different concentrations. The antitoxoplasmic activity of the drugs was first assessed with [3H]uracil, which is incorporated by the parasite but not the host cell. Pentatroxane and thiahexatroxane were the most active, exhibiting 90% inhibitory concentrations of 6.8 and 5.3 micrograms/ml, respectively. Furthermore, microscopic examination of the infected macrophages after treatment with pentatroxane, thiahexatroxane, and hexatroxanone at their respective 90% inhibitory concentrations confirmed the inhibition of intracellular growth of T. gondii. Their activities were comparable to those of pyrimethamine (1 micrograms/ml) and pyrimethamine (0.1 micrograms/ml) in combination with sulfadiazine (25 micrograms/ml). Pentatroxane and thiahexatroxane were also able to inhibit intracellular growth of T. gondii within nonprofessional phagocytes (HeLa cells), suggesting that the antitoxoplasmic activity was not caused by a macrophage-specific mechanism, such as macrophage activation. However, the 1,2,4-trioxanes were not active against extracellular T. gondii. Pentatroxane and thiahexatroxane are new, promising compounds that deserve further study to assess their usefulness for treating toxoplasmosis.

Animals↗
PubMed1989

High voltage electric pulses efficiently induce fusion of cells in monolayer culture.

High voltage electric pulses, 1000 V/cm, were found to induce cell fusion efficiently when delivered to cells growing in a monolayer culture. The maximum yield of fused cells was about 30% of cells remaining after treatment. Colonies of interspecies hybrid cells between mouse and others also appeared with a frequency of 3 X 10(-4) - 2 X 10(-5) after culturing fused cells in a selection medium that permits the growth of only hybrid cells. This method of electrofusion was applied for complementation analysis of DNA repair-deficient xeroderma pigmentosum cells. Efficient cell fusion was also observed with these human diploid fibroblasts and the resulting heterodikaryons showed a recovery of ultraviolet light-induced unscheduled DNA synthesis to the same extent as in normal cells.

Animals↗
PubMed1988

Activity of A-56268 (TE-031), a new macrolide, against Toxoplasma gondii in mice.

The activity of A-56268 (TE-031), a new macrolide, was tested in a murine model of acute toxoplasmosis. All control animals died in 8 +/- 1 days, while all mice treated with nine daily doses of A-56268 at 300 mg/kg, administered by gavage, survived. Moreover, 41.6% of the surviving mice were free from cerebral infection with Toxoplasma gondii, as assessed by brain subpassage. A-56268 is active against T. gondii in vivo, but further studies are needed to determine its usefulness in the treatment of human toxoplasmosis.

Animals↗
PubMed1988

Activity of spiramycin against Toxoplasma gondii in vitro, in experimental infections and in human infection.

The in-vitro, experimental and clinical activities of spiramycin against Toxoplasma gondii have been reviewed. In mammalian cells infected by T. gondii as in various experimental models, spiramycin definitively exerts an inhibitory antitoxoplasmic effect which, clinically, seems useful for preventing congenital toxoplasma infection during pregnancy or for reducing the inflammation in toxoplasmic chorioretinitis. However, spiramycin does not kill the parasite efficiently, and cannot be recommended for eradicating the most severe forms of toxoplasmosis.

Animals↗
PubMed1988

In vitro effects of four macrolides (roxithromycin, spiramycin, azithromycin [CP-62,993], and A-56268) on Toxoplasma gondii.

The effect of four macrolides against intracellular Toxoplasma gondii was determined in three different in vitro systems. Unactivated murine peritoneal macrophages were infected with the virulent RH strain of T. gondii. The activity of the macrolides was first measured with [3H]uracil, which is incorporated by the parasite but not the host cell. The 50% inhibitory concentrations (IC50s) and 95% confidence limits were calculated at 54 (38 to 73), 140 (98 to 201), 147 (101 to 214), and 246 (187 to 325) micron for roxithromycin, azithromycin (CP-62,993), A-56268, and spiramycin, respectively. Inhibition of Toxoplasma growth was confirmed by microscopic examination of the infected macrophages after treatment with roxithromycin. Compared with untreated controls, roxithromycin concentrations near the IC50s decreased the number of infected cells, the number of tachyzoites per vacuole, and the number of cells containing rosettes (i.e., clusters of more than eight tachyzoites). After treatment with the four macrolides, tachyzoites were released from the macrophages and subcultured in HeLa cells, which are nonprofessional phagocytes, to assess the viability of the remaining parasites. This showed that the macrolides at concentrations corresponding to four times their 90% inhibitory concentrations (IC90s) had no significant killing effect. At 8 times the IC90, roxithromycin showed an incomplete killing effect, similar to that of the combination of pyrimethamine (0.41 microM)-sulfadiazine (99.42 microM). All macrolides tested showed inhibitory effects against intracellular T. gondii, but amounts of azithromycin and A-56268 corresponding to the IC90 appeared to be toxic against the host macrophages, which might have had nonspecific activity against Toxoplasma metabolism.

Animals↗
PubMed1987

Comparative analysis of O6-methylguanine methyltransferase activity and cellular sensitivity to alkylating agents in cell strains derived from a variety of animal species.

Using 26 cultured cell lines derived from 17 different animal species, we have measured both the activity of O6-methylguanine (O6-MeG) methyltransferase (MT) in cell extracts and the sensitivity of the strains to the lethal effects of the alkylating agents, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU). The MT activity was assayed by measuring the amount of 3H radioactivity transferred from methyl-[3H]-labeled O6-MeG in DNA to acceptor protein molecules in the extracts. In all the 21 mammalian cell strains, lethal sensitivity to ACNU as measured by colony-forming ability correlated well with cellular MT activity, indicating that the major lethal ACNU damage is reparable by the MT. On the other hand, MNNG sensitivity did not necessarily correlate with the MT activity.

Alkylating Agents↗
PubMed1987

Activity of roxithromycin against Toxoplasma gondii in murine models.

Investigations into the activity of roxithromycin against murine toxoplasma infections are reviewed. Roxithromycin is an active drug against murine toxoplasmosis after intraperitoneal challenge with the RH strain of Toxoplasma gondii. Roxithromycin protected 100% of mice after five daily doses of 540 mg per kg administered by gavage. The cure rate after treatment of peritoneal infections seemed to be related to the length of the therapy. Roxithromycin also decreased the number of toxoplasma cysts, after intracerebral infection with the C56 strain and showed synergistic activity when combined with gamma interferon. Thus, roxithromycin could be a worthwhile alternative to current therapy against toxoplasma infections. Clinical studies on its activity and safety, especially in pregnancy, are warranted.

Animals↗
PubMed1987

Effect of roxithromycin on acute toxoplasmosis in mice.

Roxithromycin effectively treated acute peritoneal murine toxoplasmosis. After five doses, starting 24 h after challenge, the 100 and 50% survival doses were 540 and 336 mg/kg per day, respectively. After 14 doses, starting 3 h after challenge, the 50% survival dose was 360 mg/kg per day. Toxoplasma gondii was recovered from the brain in 59 and 28% of surviving mice treated with 5 and 14 doses, respectively.

Acute Disease↗
PubMed1987

O6-methylguanine methyltransferase activity and sensitivity of Japanese tumor cell strains to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)- 3-nitrosourea hydrochloride.

Using 40 tumor cell strains derived from various organs of Japanese tumor patients and also 12 normal cell strains, we have measured the activity of O6-methylguanine-DNA methyltransferase (MT), which can repair O6-methylguanine produced in DNA by alkylating agents. Then, the lethal sensitivities of the strains to the anti-tumor drug 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-)2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) were measured. The MT activity was assayed by measuring the 3H radioactivity transferred from the substrate DNA containing [methyl-3H]-O6-methylguanine to acceptor molecules in the cell extracts. Extracts from the majority of tumor strains and all normal cell strains contained substantial MT activity of varying degree, while the extracts of 6 tumor strains showed virtually undetectable MT activity. Hence these 6 strains were assigned as Mer-, the phenotype which is characterized by the inability to repair O6-methylguanine in DNA due to the lack of MT. The Mer- tumor strains were much more sensitive to ACNU than the rest of Mer+ strains, as measured by colony-forming ability. Furthermore, with all the tumor and normal strains tested, a good correlation was observed between MT activity and cellular resistance to ACNU. These results indicate that the frequency of Mer- strain is about 15% among Japanese tumor cell strains so far analyzed, and further suggest that MT may be the only system able to repair lethal DNA damage induced by ACNU.

Cell Survival↗
PubMedDate not supplied

Multifactorial analysis of survival in primary extremity liposarcoma.

The treatment of extremity soft tissue sarcoma is now directed at limb preservation with the addition of various adjuvant therapies to improve treatment results. To achieve this goal, a knowledge of prognostic factors for extremity soft tissue sarcoma becomes increasingly critical. The object of this study was to analyze prognostic factors for survival in patients with extremity liposarcoma. Eighty-three patients with primary localized extremity liposarcoma, admitted from 1968 to 1978, were retrospectively reviewed. Surgical resection was the primary mode of treatment. Eleven prognostic factors were analyzed. Tumor factors included: histologic subtype, tumor grade, size, depth, invasion of vital structures, and site; operative factors included: type of operation, and surgical margins; and patient factors included: symptoms, age at diagnosis, and sex. Kaplan-Meier survival curves, and univariate and stratified log-rank tests of association were performed. Independent factors for predicting survival were identified using the Cox model stepwise regression technique. In univariate analysis of the entire group of patients, 5 factors were significant for tumor mortality: tumor grade (p = 0.00005), histologic subtype (p = 0.00025), tumor size greater than or equal to 5 cm (p = 0.005), type of surgery/margin (p = 0.0001), and invasion of vital structures (p = 0.008). When associations among all factors were analyzed, it was found that many factors were interdependent. The independent prognosticators were, therefore, determined according to the Cox model technique. For the multivariate analysis, well-differentiated and lipoblastic liposarcomas were excluded because of lack of survival variation within each group. The former group had no tumor-related deaths and the latter group showed 80% tumor mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMedDate not supplied

Optimal surgical treatment of invasive lobular carcinoma of the breast.

BACKGROUND: The roles of breast conservation and surgical evaluation of the contralateral breast in the treatment of lobular carcinoma of the breast remain unclear. The aim of this study was to compare local recurrence, 5-year survival, and incidence of contralateral breast cancer in women with lobular carcinoma to that in women with infiltrating ductal carcinoma. METHODS: Women with infiltrating ductal carcinoma (IDC) and invasive lobular breast carcinoma (ILC) diagnosed during the years 1984 to 1994 were identified through a statewide tumor registry. The women were divided into groups based on their histology and treatment (breast conservation or modified radical mastectomy). The incidences of contralateral breast cancer, local recurrence, and 5-year survival were compared within each histologic group and treatment category. RESULTS: During the period 1984 to 1994, 4886 women were diagnosed with invasive lobular or ductal breast carcinoma. Of these, 316 (6.5%) had infiltrating lobular cancer. The 5-year survival rates were 68% and 71% for ILC and IDC, respectively (p = 0.5). The local recurrence rates were 2.8% and 4.3% for ILC treated with lumpectomy and axillary nodal dissection (LAND) and modified radical mastectomy (MRM), respectively, which were not significantly different from that obtained with IDC (LAND = 2.5%, MRM = 2.1%). The incidence of contralateral breast cancer during the period was 6.6% and 6.5% for ILC and IDC, respectively. CONCLUSIONS: Invasive lobular carcinoma can be safely treated with breast conservation with no difference in local recurrence or survival. In the absence of a suspicious finding on clinical or radiologic examination, routine contralateral breast intervention is not recommended.

Breast Neoplasms↗
PubMedDate not supplied

Role of cytokines in AIDS wasting.

There is now a large literature implicating cytokines in the development of wasting and cachexia commonly observed in a variety of pathophysiologic conditions. In the acquired immunodeficiency syndrome (AIDS), cytokines elicited by primary and secondary infections seem to exert subtle and sustained effects on behavioral, hormonal, and metabolic axes, and their combined effects on appetite and metabolism have been postulated to drive wasting. However, correlations of increased blood levels of a particular cytokine with wasting in AIDS have not been consistent observations, perhaps because cytokines act principally as paracrine and autocrine hormones, as well as indirectly by activating other systems. A better understanding of the mechanisms underlying the catabolic effects of cytokines in clearly needed if more efficacious strategies are to be developed for the prevention and treatment of wasting in AIDS. In this review we first examine the interacting factors contributing to the AIDS wasting syndrome. We then analyze the complex and overlapping role of cytokines in the pathophysiology of this condition, and put forward a number of hypotheses to explain some of the most important features of this syndrome.

Cachexia↗
PubMedDate not supplied

Quassinoids exhibit greater selectivity against Plasmodium falciparum than against Entamoeba histolytica, Giardia intestinalis or Toxoplasma gondii in vitro.

The in vitro activities of a series of quassinoids against Plasmodium falciparum, Entamoeba histolytica, Giardia intestinalis and Toxoplasma gondii have been compared with their in vitro cytotoxic effects against KB cells (human epidermoid carcinoma of the nasopharynx). All of the compounds tested were more toxic to KB cells than to G. intestinalis, but four (ailanthinone, bruceine D, brusatol and glaucarubinone) were slightly less toxic to KB cells than to E. histolytica. Glaucarubinone was similarly more toxic to intracellular T. gondii than to KB cells but ailanthinone was more selective (36 times more toxic to T. gondii than to KB cells). All of the compounds were more toxic to P. falciparum than to KB cells; the most selective quassinoids--glaucarubinone, bruceine D, ailanthinone and brusatol--were found to have toxicity/activity ratios of 285, 76, 48 and 32 respectively. These results suggest that quassinoids have a selective action on P. falciparum. Further studies to elucidate the basis for this are in progress.

Animals↗