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Biomedical subjects

R Kim

Publications and source records attributed to R Kim.

At least 163 records · Page 9Linked to original sources
PubMed1992

Resolution of type 1 reaction in multibacillary Hansen's disease as a result of treatment with cyclosporine.

Type 1 Hansen's disease reaction (reversal reaction) is believed to result from a change in the immune response in patients with borderline Hansen's disease. The only effective therapy for significant type 1 reactions has been systemic corticosteroid therapy. Cyclosporine is an immunosuppressive drug which has been widely used in organ transplantation. We report a case of type 1 reaction complicating borderline lepromatous Hansen's disease. Cyclosporine therapy resulted in prompt and sustained resolution of the reaction. The possible mechanism of action of cyclosporine and the implications regarding the immunopathogenesis of type 1 reaction are discussed.

Adult↗
PubMed1991

mRNA expression of topoisomerase II in human tumors and normal tissues.

The cellular levels of topoisomerase II expression were compared between 10 fresh human tumors and normal tissues to predict the selective anticancer effect of its inhibitors such as adriamycin and VP-16. Topoisomerase II expression was observed in 9 of the 10 tumor tissues (90.0 per cent), 3 of which showed extremely high levels, whereas only 5 of the normal tissues (50.0 per cent) expressed any cellular topoisomerase II and the levels were not higher than those seen in the cancer cells. Six of the 9 positive tumors showed a higher level of topoisomerase II expression than the normal tissues, while the other 3 showed the same level. It can be interpreted from these results that topoisomerase II inhibitors could be effective in cancer patients due to the greater level of this enzyme in tumor cells than in normal tissues. Thus, it is suggested that a comparative analysis of topoisomerase II expression between tumors and normal tissues may be useful for predicting the selective cytotoxicity of topoisomerase II inhibitors in clinical practice.

DNA Topoisomerases, Type II↗
PubMed1991

Clinical significance of P-glycoprotein expression analyzed by immunohistochemical staining in cancer tissues.

P-glycoprotein is a transmembrane protein with increased drug efflux from resistant cells, which is encoded by the MDR1 gene. An overexpression of P-glycoprotein has been reported to correlate with the degree of resistance to anticancer agents, especially to adriamycin. In this study, the expression of P-glycoprotein was analyzed immunohistochemically by using a monoclonal antibody, MRK16 against P-glycoprotein in 18 fresh human tumors. The expression of P-glycoprotein was detected in eight (44 per cent) tumor specimens out of 18 patients. Although six (75.0 per cent) of the 8 P-glycoprotein positive tumors were resistant to adriamycin, the other two tumors showed clinical responses. Furthermore, five (50.0 per cent) of the 10 P-glycoprotein negative tumors exhibited positive clinical responses. These results suggest that P-glycoprotein expression may not be a useful marker to predict intrinsic resistance to adriamycin in fresh human tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Prediction of the resistance of human tumors to adriamycin by chemosensitivity tests and DNA analysis of the multidrug resistance gene.

In order to predict natural resistance to Adriamycin (ADM), the amplification of multidrug resistance gene 1 (MDR1) was investigated in 50 human cancer specimens using Southern blot analysis. Genomic DNA was extracted from both human solid tumors and adjacent normal tissues for the analysis. MDR1 gene amplification was not observed in any of the patients tested, including 5 patients in whom ADM was not clinically effective. On the other hand, chemosensitivity tests performed on the tumor cells of these 5 patients indicated resistance to ADM. Our results therefore indicate that MDR1 gene amplification is rarely seen among clinical samples and that conventional chemosensitivity tests might be more useful for the prediction of ADM resistance in cancer patients than the analysis of MDR1 gene amplification.

Blotting, Southern↗
PubMed1990

Prenylation of mammalian Ras protein in Xenopus oocytes.

Ras protein requires an intermediate of the cholesterol biosynthetic pathway for posttranslational modification and membrane anchorage. This step is necessary for biological activity. Maturation of Xenopus laevis oocytes induced by an oncogenic human Ras protein can be inhibited by lovastatin or compactin, inhibitors of the synthesis of mevalonate, an intermediate of cholesterol biosynthesis. This inhibition can be overcome by mevalonic acid or farnesyl diphosphate, a cholesterol biosynthetic intermediate downstream of mevalonate, but not by squalene, an intermediate after farnesyl pyrophosphate in the pathway. This study supports the idea that in Xenopus oocytes, the Ras protein is modified by a farnesyl moiety or its derivative. Furthermore, an octapeptide with the sequence similar to the C-terminus of the c-H-ras protein inhibits the biological activity of Ras proteins in vivo, suggesting that it competes for the enzyme or enzymes responsible for transferring the isoprenoid moiety (prenylation) in the oocytes. This inhibition of Ras prenylation by the peptide was also observed in vitro, using both Saccharomyces cerevisiae and Xenopus oocyte extracts. These observations show that Xenopus oocytes provide a convenient in vivo system for studies of inhibitors of the posttranslational modification of the Ras protein, especially for inhibitors such as peptides that do not penetrate cell membranes.

Amino Acid Sequence↗
PubMed1990

Molecular analysis of insertion/deletion mutations in protein 4.1 in elliptocytosis. II. Determination of molecular genetic origins of rearrangements.

Protein 4.1 is an approximately 80-kD structural protein in the membrane skeleton which underlies and supports the erythrocyte plasma membrane. The preceding companion paper presents a biochemical study of two abnormal protein 4.1 species from individuals with the red blood cell disorder, hereditary elliptocytosis. These variants, "protein 4.1(68/65)" and "protein 4.1(95)," have altered molecular weights due to internal deletions and duplications apparently localized around the spectrin-actin binding domain. Here we use polymerase chain reaction (PCR) techniques to clone and sequence the corresponding mutant reticulocyte mRNAs, and correlate the deletion/duplication end points with exon boundaries of the gene. Protein 4.1(68/65) mRNA lacks sequences encoding the functionally important spectrin-actin binding domain due to a 240 nucleotide (nt) deletion spanning the codons for Lys407-Gly486. Protein 4.1(95) mRNA encodes a protein with two spectrin-actin binding domains by virtue of a 369 nt duplication of codons for Lys407-Gln529. These deletions and duplications correspond to gene rearrangements involving three exons encoding 21, 59, and 43 amino acids, respectively. The duplicated 21 amino acid exon in the 4.1(95) gene retains its proper tissue-specific expression pattern, being spliced into reticulocyte 4.1 mRNA and out of lymphocyte 4.1 mRNA.

Base Sequence↗
PubMed1990

Expression of the multidrug resistance gene in human tumors.

The expression of MDR1 gene was investigated in human solid tumors with respect to adriamycin resistance. Forty fresh human surgical specimens were analyzed by RNA dot blot assay for their expression of the human MDR1 gene and by immunohistological staining using a monoclonal antibody against P-glycoprotein (MDR1 gene product). The MDR1 mRNA level was increased in 11 cases of 40 cancer patients, including three rectal cancers, two breast cancers, two gastric cancers, one colon cancer, one renal cell carcinoma, one gall bladder cancer and one malignant lymphoma of stomach. However, considerable variation of the MDR1 mRNA level was noted among cancers of a specific type. Immunohistochemical studies with the monoclonal antibody were shown to be positive in 18 tumors. In all tumors tested, the MDR1 mRNA level and the immunohistochemical analysis showed a significant correlation. However, two of five tumors which resisted adriamycin treatment were found to be negative in MDR1 transcript, but positive in immunohistological analysis. These results indicate that immunohistochemical analysis would be more sensitive for detecting P-glycoprotein-expression, and that resistance to adriamycin, being multifactorial, can be associated at least, in part with the increased amount of MDR1 gene product.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Immunochemical demonstration of tropomyosin in the neurofibrillary pathology of Alzheimer's disease.

The focus of research on the neurofibrillary pathology (NFP) of Alzheimer disease has been not only to determine the component forming the paired helical filaments but also to determine whether they result from abnormal processes affecting a single protein. Therefore, although these studies have lead to controversy concerning the respective contribution of components of microtubules and neurofilaments, there has been essentially no consideration of whether other cytoskeletal systems might also be involved and of what are the common features for the incorporated components. Particularly relevant to this issue is our finding that several antisera raised to either skeletal or smooth muscle tropomyosin, a microfilament component, intensely recognize NFP. These antibodies continue to recognize NFP after affinity purification to tropomyosin or paired helical filament fractions. We show that the antibodies do not recognize NFP due to cross-reactivity with the previously identified NFP components related to neurofilaments and microtubules, tau, and MAP2, or neurofilament proteins because the antisera did not recognize these proteins on immunoblots or were not adsorbable by the proteins. Ultrastructural analysis of the immunoreaction showed that tropomyosin-related epitopes were clustered rather than uniformly distributed along paired helical and straight filaments. Although the distribution suggests that tropomyosin is an NFP-associated protein, its retention by paired helical and straight filaments after detergent extraction indicates that it is an integral component strongly and specifically associated with the filaments characteristic of NFP. These findings indicate that NFP involves the three primary neuronal cytoskeletal filament systems, microtubules, neurofilaments, as well as microfilaments, and therefore that NFP probably results from the reorganization of these normal filaments that interact to comprise the cytomatrix and may continue this interaction under the pathologic condition of Alzheimer's disease to generate novel, abnormal polymers.

Actin Cytoskeleton↗
PubMed1989

Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans.

The activity of an oncoprotein and the secretion of a pheromone can be affected by an unusual protein modification. Specifically, posttranslational modification of yeast a-factor and Ras protein requires an intermediate of the cholesterol biosynthetic pathway. This modification is apparently essential for biological activity. Studies of yeast mutants blocked in sterol biosynthesis demonstrated that the membrane association and biological activation of the yeast Ras2 protein require mevalonate, a precursor of sterols and other isoprenes such as farnesyl pyrophosphate. Furthermore, drugs that inhibit mevalonate biosynthesis blocked the in vivo action of oncogenic derivatives of human Ras protein in the Xenopus oocyte assay. The same drugs and mutations also prevented the posttranslational processing and secretion of yeast a-factor, a peptide that is farnesylated. Thus, the mevalonate requirement for Ras activation may indicate that attachment of a mevalonate-derived (isoprenoid) moiety to Ras proteins is necessary for membrane association and biological function. These observations establish a connection between the cholesterol biosynthetic pathway and transformation by the ras oncogene and offer a novel pharmacological approach to investigating, and possibly controlling, ras-mediated malignant transformations.

Amino Acid Sequence↗
PubMed1989

Induction of cytotoxicity from fresh splenocytes after in vivo administration of cyclophosphamide. Importance of long-term culture with high-dose recombinant interleukin-2.

Cyclophosphamide, combined with lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2), is known to mediate regression of tumors, but the effects of cyclophosphamide on the subsequent generation of LAK cells are unclear. It was the aim of the experiments in this paper to determine whether fresh splenocytes cultured with rIL-2 would maintain or regain their cytotoxicity in vitro after being exposed to the cytotoxic agent cyclophosphamide in vivo. Functional monitoring of splenocytes after in vitro incubation with rIL-2 was performed at various times through chromium-release assays, thymidine assays and cell-cycle analysis. Chromium-release assays determined that the cytotoxicity of cultured splenocytes returned to normal after 12 days of in vitro culture with rIL-2. The thymidine assays indicated a normal rate of uptake of thymidine after 7 days in culture, while the cell cycle was still abnormal by day 12 of culture. The growth and expansion of rIL-2-activated splenocytes after different times of in vitro culture indicated a return to normal compared to control animals after 7 days of continuous in vitro exposure to rIL-2. It is concluded that murine splenocytes can demonstrate cytotoxicity after exposure to cyclophosphamide, through prolonged continuous in vitro culture with rIL-2. Since cyclophosphamide did not jeopardize the production of splenocyte cytotoxic effectors generated with rIL-2, it appears to be a strong contender for use in chemoimmunotherapy protocols.

Animals↗
PubMed1989

The histological assessment and evaluation of a 4 day subrenal capsule assay by the percentage inhibition of DNA/protein.

A four day subrenal capsule assay was investigated in order to determine its ability to clinically predict tumor chemosensitivity. To establish more objective and accurate evaluation criteria, a histological assessment and measurement of the DNA and protein content of excised tumor implants was conducted in ddY mice. The histological studies provided qualitative results concerning the percentage of cancer cells in the xenograft, the number of mitoses, the amount of necrosis, and the extent of lymphocytic infiltration. The DNA content was measured by a modified version of the Schmidt-Thannhauser-Schneider method and the protein content was estimated using the Bio-Rad protein assay. The percentage of cancer cells in the xenograft correlated poorly with the relative increase in tumor size, weight and the percentage inhibition of DNA/protein (per cent DNA/protein), however, the per cent DNA/protein correlated well with the clinical effects in 85.7 per cent of the tumors studied. Moreover, the histological assessment information was only consistent with those results obtained for per cent DNA/protein in the control group.

Animals↗
PubMed1989

Chemosensitivity tests in colorectal cancer patients.

In order to assess the usefulness of chemosensitivity tests in the treatment of colorectal cancer, 71 tumor specimens were tested for chemosensitivity in the following assays: nude mouse isotope assay (NMIA), subrenal capsule assay (SRCA), human tumor clonogenic assay (HTCA) and adenosine triphosphate inhibition assay (ATPA). The agents examined were: mitomycin C (MMC), 5-fluorouracil (5-FU), cyclophosphamide (CPM), adriamycin (ADM) and cis-diamminedichloroplatinum (CDDP). The evaluability rates were 90.8, 93.9 and 92.3 per cent in NMIA, SRCA and ATPA, respectively, but only 42.9 per cent in HTCA. The tumor response rates were 50.8, 45.2, 16.7 and 33.3 per cent in NMIA, SRCA, HTCA and ATPA, respectively. Individual drug sensitivity rates differed among all 4 assays, ranging from 0 to 33.3 per cent. In the arbitrary judgment of the 4 assays, the most sensitive agent was CDDP, followed by CPM, ADM, 5-FU and MMC. In the prospective study, predictive accuracy rates of the clinical responses were 81.3, 66.7, 100, 100 and 76.5 per cent in NMIA, SRCA, HTCA, ATPA and the arbitrary judgment, respectively. A significant correlation between the survival time and the results of SRCA was detected retrospectively. These results suggested that colorectal cancer might not be completely resistant to anticancer agents, and that chemosensitivity tests might be useful in the individual therapy of colorectal cancer patients.

Antineoplastic Agents↗
PubMed1989

Redesigning a sweet protein: increased stability and renaturability.

Monellin is one of two natural proteins from African berries with potent sweet taste. Monellin is the smaller of the two, and consists of two peptides. The protein loses sweetness when heated above 50 degrees C under acidic pH. Based on the crystal structure of monellin we have fused the two chains into a single chain using several different linkers copied and 'transplanted' from the same molecule. One of the newly designed proteins is as potently sweet as the natural one, is more stable upon temperature or pH changes, and renatures easily even after heating to 100 degrees C at low pH.

Amino Acid Sequence↗
PubMed1989

[Comparative study on the anticancer activities of KW2149 and mitomycin C against human tumor xenografts using subrenal capsule assay].

The anticancer activity of KW2149, a new derivative of mitomycin C (MMC), was investigated against 5 human tumor xenografts derived from digestive organs using 4-day subrenal capsule assay (SRCA). Normal immunocompetent mice were used in this assay. For the comparative study, KW 2149 and MMC were administered intraperitoneally for 3 days after implantation, and the anticancer activity and the weight loss of mice were evaluated. The total doses were determined as 1/2, 1/3 and 1/4 of LD50 value of each anticancer agent. The anticancer activities of the two drugs were almost the same with no significant difference in 3 xenografts. Thus, it may be suggested the difference of the anticancer spectrum between the two drugs. The anticancer activity of KW2149 indicated higher correlation with the administered doses as compared with MMC. The toxicity of KW2149 was almost the same as MMC according to the weight loss of mice.

Animals↗
PubMed1989

[Combination chemotherapy of CPM-MTX-5-FU in non-resectable and recurrent cancer patients].

Fifty-two non-resectable and recurrent cancer patients with prior treatment, were entered in this study; 1 esophageal, 33 gastric, 1 duodenal, 4 colorectal, 2 pancreatic, 2 bile duct, and 9 breast cancer. The protocol of this therapy was as follows: On day 1, 500 mg/body cyclophosphamide (CPM) was administered by drip infusion, and on day 2, 200 mg/m2 methotrexate (MTX) was infused intravenously for 30 min; immediately after, 500 mg/body 5-fluorouracil (5-FU) was injected by bolus infusion for 5-10 min. On day 3, 24 hours after MTX administration, leucovorin rescue was added. This combination chemotherapy was repeated every two weeks. As a result, 35 of 52 patients were evaluable and the response rate (CR + PR) was investigated; 2/21 (9.5%) for gastric, 2/7 (28.6%) for breast, and 0% for miscellaneous. As complications for side effect, general fatigue, anorexia, nausea, vomiting and stomatitis were observed symptomatically, and leukopenia and thrombocytopenia were recognized in laboratory data as dose limiting factors.

Anorexia↗
PubMed1989

[Comparison of succinic dehydrogenase inhibition test with adenosine triphosphate inhibition assay for human solid tumors as in vitro chemosensitivity tests].

In order to determine the most effective anticancer agents for individual human tumor, succinic dehydrogenase inhibition test (SDI-T) and adenosine triphosphate inhibition assay (ATP-A) as in vitro chemosensitivity tests were performed. Fifty tumors and 57 tumors derived from cancer patients surgically methods were examined by SDI-T and ATP-A respectively. As the results, the evaluable rate was 70% by SDI-T and 94.7% by ATP-A, respectively. With SDI-T, the positive rate against all tumors was 51.4% in mitomycin-C (MMC), 42.9% in adriamycin (ADM), 20.0% in 5-fluorouracil (5-FU), 54.3% in cis-diamminedichloroplatinum (CDDP). On the other hand, with ATP-A, that was 20.4% in MMC, 29.5% in ADM, 20.6% in 5-FU, 20.4% in CDDP, respectively. Retrospective and prospective clinical trials were also carried out to determine the usefulness of both assays. With SDI-T, overall predictive accuracy rate was 57.1% while with ATP-A that was 88.9%. Furthermore, the rates of sensitivity for the same tumors using SDI-T and ATP-A were compared. The rate of the same sensitive cases in both assays were 30% with MMC, 70% with 5-FU, 42.1% with ADM, 36.8% with CDDP, respectively. In conclusion, it is suggested that ATP-A was more useful than SDI-T as in vitro chemosensitivity test to determine the most adequate drug for cancer patients.

Adenosine Triphosphate↗