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Biomedical subjects

I R Hart

Publications and source records attributed to I R Hart.

At least 127 records · Page 7Linked to original sources
PubMed1987

Long-term follow-up of ophthalmic Graves' disease.

Sixteen patients with ophthalmic Graves' disease (clinically euthyroid with ophthalmopathy or exophthalmos) were followed up for 4.3 to 14.3 (mean 9.1) years to determine whether thyroid dysfunction developed and whether their ophthalmopathy progressed, regressed or remained stable. Five patients (31%) manifested hyperthyroidism or hypothyroidism, all before the end of the fifth year of follow-up. The ophthalmopathy was mild, and none of the patients required specific treatment. The thyroid function of patients with ophthalmic Graves' disease should be periodically monitored for at least 5 years.

Adolescent↗
PubMed1987

Can cancer chemotherapy enhance the malignant behaviour of tumours?

Cancer chemotherapy is currently undergoing an intensive reappraisal because of its unimpressive performance against the major common cancers. There are a number of possible reasons for this lack of success; one considered here is that under some circumstances anti-neoplastic drug treatment actually increases the malignant behaviour of tumours. Support for this idea comes mainly from experimental studies in which drug treatments increased metastatic spread. Investigation of this phenomenon shows that drug induced modifications of the host, including immunosuppression and vascular damage, can indeed facilitate metastasis. In addition, new data are presented demonstrating that the direct action of drugs on the tumour cells themselves can have similar enhancing effects. The possible mechanisms underlying such direct effects are discussed and the ability of anti-cancer drugs to cause genetic mutations, amplify genes, and alter gene expression are considered. While the nature and extent of this facilitation of tumour malignancy is not fully understood, it is suggested that this possibility should be considered in the design of treatment protocols.

Animals↗
PubMed1987

Value of free thyroxine (FT4), free triiodothyronine (FT3), and sensitive thyrotropin (TSH) assay in the assessment of optimal thyroxine therapy.

We describe a sensitive thyrotropin (TSH) assay in the evaluation of thyroxine replacement therapy. Patients taking varying amounts of L-thyroxine replacement doses were studied using a thyrotropin-releasing hormone (TRH) test and a sensitive TSH assay as the indices of optimal replacement therapy. There were no differences in the mean thyroxine doses of those patients who had a normal TRH response and those who had a flat response. Similarly there were no significant differences in the serum free thyroxine (FT4), free triiodothyronine (FT3), or total triiodothyronine (TT3) levels between these two groups. The patients in both groups had normal basal serum TSH values as measured by a standard, HTSH RIABEAD (Abbott) method. However, serum TSH values, as measured by a sensitive TSH3 MAIACLONE (Serono) immunoradiometric method, were subnormal in all patients with flat TRH responses. The TSH (Serono) assay provided the best single blood test of optimal thyroxine replacement.

Adult↗
PubMed1986

Enhancement of experimental metastasis by pretreatment of tumour cells with hydroxyurea.

The effect of treatment with hydroxyurea (HU), on subsequent experimental metastasis formation by cells of 3 murine melanoma lines has been examined. In vitro treatment of B16-F1, B16-F10 and K-1735-clone 19 cells with 0.1 mM or 0.3 mM HU, followed by a period of recovery in drug-free medium, resulted in a significant increase in the number of lung nodules formed in syngeneic mice following i.v. injection of the cells. The maximum effect obtained was observed when cells were injected 6 hr after removal of HU and it occurred in spite of the cytotoxicity of the doses used. Six hours after release from treatment with 0.3 mM HU cells were synchronized in the G2 phase of the cell cycle but the consequent increase in cell volume was not responsible for increased metastasis through enhancement of tumour-cell arrest, since lodgement of 51Cr-labelled, HU-treated cells was no greater than that of control cells. The results obtained suggest that the chemotherapeutic agent HU may facilitate tumour progression via a direct action on neoplastic cells.

Animals↗
PubMed1986

The effect of interferon on experimental metastases in immunocompetent and immunodeficient mice.

A recombinant human hybrid alpha interferon (rIFN-alpha A/D) with antiviral, immunomodulating and cell-growth-inhibitory activity on murine cells strongly inhibited the development of experimental pulmonary metastases of the Colo 26 adenocarcinoma in BALB/c mice. Twenty-one days after i.v. injection of 5 X 10(4) cells, 8/8 control mice had greater than 200 lung tumour nodules whereas 1/6 mice receiving 500 ng rIFN-alpha A/D had one lung tumour nodule and the other 5 mice were tumour-free. Equally strong inhibition was seen in immunodeficient BALB/c nu/nu (athymic) and beige nu/nu (athymic and NK-deficient) mice. Scheduling experiments in vivo showed that the most important time of IFN treatment was from the day of tumour cell injection to day 5, although statistically significant reductions in lung tumour nodule number and lung weight were seen even when IFN treatment was started 7 days after cell injection. rIFN-alpha A/D was cytostatic to Colo 26 in vitro, causing 50% or more inhibition of cell growth or colony number at IFN levels that could be achieved in the sera of IFN-treated mice. Although rIFN-alpha A/D stimulated NK-cell activity in BALB/c mice, Colo 26 cells were resistant in vitro to such cells whether from control or IFN treated mice.

Adenocarcinoma↗
PubMed1986

Cell uptake, distribution and response to aluminium chloro sulphonated phthalocyanine, a potential anti-tumour photosensitizer.

The uptake, retention and effects of aluminium chloro sulphonated phthalocyanine (AlSPc) were measured in two cell lines, UV-2237 a murine fibrosarcoma and the non-tumorigenic NIH/3T3 fibroblast line. The behaviour of cells treated with AlSPc was compared with that of those treated with haematoporphyrin derivative (HpD), a photosensitizer often used in photodynamic therapy (PDT) of cancer. AlSPc absorbs light strongly in the red region, is taken up by cells in a dose dependent fashion and is retained in vitro over a period of days (5 days after exposure greater than 40% remains cell-associated versus less than 25% of HpD). Additionally AlSPc was less cytotoxic to cells, maintained in darkness or exposed to room light, compared to HpD (100% viability versus 0% viability 3 days after 60 min exposure to room light). However red light (approximately 600-700 nm) caused greater toxicity in AlSPc-treated cells (100%) than in similarly exposed HpD-treated cells (less than 60%). No significant differences were detected between the responses of the fibrosarcoma and the fibroblast cell lines. These characteristics of AlSPc suggest that it may prove to be a useful photosensitizer for PDT of cancer and this possibility is discussed.

Animals↗
PubMed1986

Enhanced experimental metastatic capacity of a human tumor line following treatment with 5-azacytidine.

We have studied the effect of the nucleoside analogue 5-azacytidine (5-azaC) a known activator of gene expression, on the metastatic behavior of the human melanoma cell line DX3. After exposure to 3 microM 5-azaC for 24 h cells were carried through five subcultures before being tested for their metastatic capacity. Following i.v. injection in BALB/c nude mice, cells treated with 5-azaC showed a 40-fold increase in the number of lung tumor nodules as compared to that obtained with control cells. Tumors resulting from 5-azaC-treated cells exhibited a 5-fold increase in mitotic figures, considerable cellular pleomorphism, and variation in the histological character of the individual nodules. These in vivo differences were not reflected in vitro where treated and untreated cells showed no significant differences in morphology, karyotypes, growth rates, saturation densities, or plating efficiencies. Cells populating the lung tumor nodules retained their increased metastatic capacity through successive cycles of growth in vitro followed by reinjection into nude mice and indeed the ability of the cell lines to form lung tumors was increased with the succeeding cycles in vivo. These cell lines, each established from individual tumor nodules, maintained a human karyotype and reacted positively with human-specific antiserum. Characterization of these lines showed that while there were no alterations in in vitro growth behavior the selected lines exhibited a decreased latency period for s.c. tumor formation, increased retention in the lungs following i.v. injection, and enhanced lung nodule formation (60- to 80-fold compared to control cells). Examination of genomic DNA showed that treatment with 5-azaC brought about a significant decrease (50%) in the percentage of methylated cytosine residues but this extensive hypomethylation was not maintained in the lung tumor nodule-derived cell lines.

Animals↗
PubMed1986

DNA methylation levels in human and murine melanoma cell lines of varying metastatic potential.

DNA methylation levels were measured in a series of murine and human melanoma cell lines consisting of matched variants of low and high experimental metastatic capacity. The percentage of cytosine residues modified to 5-methylcytosine ranged between 2.13-3.92% in these lines. Ten cell lines were established in culture from individual lung tumor nodules produced in nude mice by i.v. injection of DX-3 human melanoma cells. Upon reinjection into groups of nude mice the individual lines manifested marked diversity for lung nodule formation (median number of pulmonary tumor nodules ranging from less than 10/group-greater than 100/group). DNA methylation levels in these lines were also heterogeneous (range 1.59 +/- 0.13 (SD)-4.04 +/- 0.15%) but no correlation was detected between methylation status of the genomic DNA and metastatic capacity.

5-Methylcytosine↗
PubMed1986

Increased experimental metastatic capacity of a murine melanoma following induction of differentiation.

Because of the interest in possible links between defective differentiation and cellular malignancy, the effects were examined of induced cell differentiation upon the experimental metastatic potential of the sublines F1 and F10 of the B16 mouse melanoma. These cell lines normally have low and high rates, respectively, of colonization of the lungs of mice after i.v. injection. Cellular differentiation was assessed by pigmentation and tyrosinase activity. In both cell lines, low and high levels of differentiation could reproducibly be generated by culture, respectively, at a low extracellular pH and at a higher pH in the presence of a melanocyte-stimulating hormone. Surprisingly, in both lines the cells grown under conditions promoting differentiation showed a markedly higher rate of experimental metastasis, despite their slower proliferation in culture and in subcutaneous tumor implants, than the poorly differentiated cells. Radiolabeled well- and poorly pigmented cells were not initially deposited at significantly different rates in the lungs of mice after i.v. injection. However, subsequent retention in the lungs fell more quickly for the poorly differentiated cells. As indicated by tests in vitro, this difference appears not to be due to differential cytotoxicity by either host macrophages or natural killer cells, and it is under further study.

Animals↗
PubMed1985

Expression of collagenase IV (basement membrane collagenase) activity in murine tumor cell hybrids that differ in metastatic potential.

Expression of a basement membrane collagen-degrading metalloprotease activity (collagenase IV) was studied in a series of murine cell hybrids derived from fusions between highly metastatic cells (B16-F10RR) or moderately metastatic cells (UV-2237RR) and tumorigenic cells (K-1735 clone 16) or normal cells [peritoneal macrophages (PEC) or C3H mouse embryo fibroblasts (C3H-F)]. The collagenase IV activity of the parent cells and the hybrids was assayed in vitro and compared to the metastatic propensity of the same cells evaluated in both syngeneic (C57BL/6 X C3H/HeN)F1 mice and BALB/c nude mice. The level of collagenase IV activity secreted by the parent lines correlated with their metastatic capacity. The highly metastatic B16-F10RR line secreted the highest enzyme activity, whereas the tumorigenic but nonmetastatic K-1735 clone 16 and the normal parents PEC and C3H-F secreted the lowest enzyme activity. The enzyme activity was completely inhibited with EDTA. The hybrid derived from fusion of cells from two metastatic cell lines as well as hybrids derived from a metastatic and a nonmetastatic tumor cell line expressed higher levels of collagenase IV activity than either parent, and this expression was associated with a high ability to produce metastases in both nude and syngeneic mice. Fusion of metastatic cells with normal cells produced hybrid cells that exhibited suppression of both collagenase IV activity and metastatic capacity. Collagenase IV activity and metastatic propensity can, therefore, be altered by somatic cell hybridization; in the series of hybrids examined in these experiments the expression of type IV collagen-degrading metalloprotease activity and the metastatic ability were closely correlated, which suggests that collagenase IV activity and other properties required for metastasis are genetically linked.

Animals↗
PubMed1985

Species variability for toxicity of free and liposome-encapsulated muramyl peptides administered intravenously.

Muramyl dipeptide and muramyl tripeptide in free form or encapsulated within multilamellar liposomes were injected intravenously into (C57BL/6 X C3H)F1 mice and strain 2 guinea pigs to evaluate their potential acute, subacute, or chronic toxicity. Animals received either single or multiple (X 3, X 4, X 6, X 8) injections. A definite species variation was established with regard to the toxic nature of muramyl peptides. Mice failed to exhibit any changes of a clinical, biochemical, functional, or morphological nature in response to repeated intravenous administrations of high doses of muramyl peptide (free or in liposomes). In contrast, strain 2 guinea pigs were very sensitive to muramyl peptide, regardless of the dose or number of injections, or whether it was given in liposomes or as micelles (free form). Most guinea pigs exhibited vascular pathology reminiscent of the Schwartzman phenomenon. Further toxicity studies of muramyl peptides administered at relevant biological doses are recommended, as well as studies aimed at elucidating the reasons for the species variations.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

The early development of transient and permanent hypothyroidism following radioiodine therapy for hyperthyroid Graves' disease.

The outcome in 110 patients first treated with radioiodine (mean dose 6.56 mCi) for hyperthyroid Graves' disease in 1980 was reviewed. In 23% of the patients the disease had not been controlled by the initial dose after 3 months, and 17% were given one or two more doses. Within 2 years 65% of the patients required replacement thyroxine therapy. Although about half of the patients were biochemically hypothyroid 3 months after the last dose of iodine 131, this condition was transient in a third of them; five of these patients even became hyperthyroid again. Patients with transient, as opposed to permanent, hypothyroidism at 3 months tended to be clinically euthyroid but to have residual palpable thyroid tissue and only a modest reduction in the serum thyroxine level. It is therefore recommended that patients not overtly hypothyroid 3 months after treatment with 131I be observed still longer before thyroxine replacement therapy is instituted.

Adult↗
PubMed1984

Expression of cell surface P-glycoprotein by an adriamycin-resistant murine fibrosarcoma.

Analysis of the cell membrane of Adriamycin (doxorubicin)-resistant UV-2237 ADMR murine fibrosarcoma cells revealed a 170,000-dalton component that is not found in the drug-sensitive parent or revertant cells. Immunoblot (Western blot) analysis showed that this component is similar to the 170,000-dalton P-glycoprotein found on the surface of Chinese hamster ovary cells that exhibit multidrug resistance. Thus, multidrug resistance and P-glycoprotein expression apparently can occur in a wide variety of cells, including the metastatic murine solid tumor cell line described here.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

Correlation of tumor growth inhibitory activity of macrophages exposed to adriamycin and adriamycin sensitivity of the target tumor cells.

Variant cell lines of the murine fibrosarcoma UV-2237, selected for doxorubicin [adriamycin (ADM)] resistance, were used to study the tumoricidal activity of macrophages that had been exposed to ADM. Free ADM (0.01-1 microgram/ml) was cytotoxic to the sensitive UV-2237M parent and to the partially sensitive UV-2237M-revertant cell lines, whereas the ADM-resistant UV-2237M ADMR line was unaffected by these levels of ADM. Macrophages harvested from the peritoneal cavities of mice given ip injections of 10 mg ADM/kg body weight 1 day or 4 days previously inhibited proliferation of the 3 cell lines, an effect that was directly correlated to the degree of ADM sensitivity of each cell line. Macrophages exposed in vitro to ADM (from 0.01 to 1 microgram/ml) inhibited the growth of, and eventually were cytolytic to, the parent and the revertant cell lines; these ADM-exposed macrophages did not affect the UV-2237M-ADMR cell line. The correlation between the antitumor effects of macrophages exposed to ADM and the ADM susceptibility of tumor cells suggests that ADM-exposed macrophages exert their effect by the release or transfer of the stored drug.

Animals↗