Biomedical subjects

T Tsuruo

Publications and source records attributed to T Tsuruo.

At least 253 records · Page 14Linked to original sources

PubMed1995

Glucose-regulated stresses confer resistance to VP-16 in human cancer cells through a decreased expression of DNA topoisomerase II.

Glucose-regulated proteins (GRPs) are induced in cells by a variety of stress conditions such as treatment with 2-deoxyglucose, glucosamine, or the calcium ionophore A23187. We found that resistance to topoisomerase II (topo II) inhibitors, VP-16 and adriamycin, was induced by these treatments in human colon cancer HT-29 cells. Similar VP-16 resistance occurred in human ovarian cancer A2780 and breast cancer MCF-7 cells. The VP-16 resistance was reversible, since the sensitivity of the cells to VP-16 recovered within 24 h after the stresses were removed. Western blotting analysis showed that under these stress conditions the cellular contents of topo II alpha were decreased. The decreased expression of topo II was reversed to control levels within 24 h following removal of the stresses. The decrease in topo II levels under the stress conditions correlated well with the induction of GRP78 and 94. The close correlation between topo II and GRPs suggests that topo II is a protein sensitive to the glucose-regulated stresses. Since hypoxia and nutrient deprivation, which are also GRP-inducing conditions, could occur naturally in the solid tumors, the stress-associated cellular resistance through decrease in topo II levels may be a mechanism of the natural resistance of the solid tumors to topo II-directed chemotherapy.

Antineoplastic Agents, Phytogenic↗

PubMed1995

A recessive mutant of the U937 cell line acquired resistance to anti-Fas and anti-p55 tumor necrosis factor receptor antibody-induced apoptosis.

Human monocytic leukemia U937 cells readily undergo apoptosis when cells are treated with various stimuli including antitumor agents, tumor necrosis factor (TNF)-alpha and anti-Fas antibody. However, the signal transduction mechanism resulting in apoptosis is unclear. To study the mechanism of apoptosis, we isolated and characterized a mutant, UK110, from U937 cells, which was resistant to TNF-alpha and anti-Fas antibody-induced apoptosis but was less resistant to etoposide-induced apoptosis. TNF-alpha induced signals are mediated by two types of TNF receptors (TNFR), p55- and p75-TNFR, and p55-TNFR is homologous to the Fas antigen. Interestingly, UK110 cells showed resistance to apoptosis by agonistic anti-p55-TNFR antibody, indicating that UK110 cells were resistant to Fas- and p55-TNFR-mediated apoptosis. Because expression of apoptosis-associated molecules, such as c-Myc, Bcl-2, and Bax, was similar between U937 and UK110 cells an undetermined pathway for apoptosis through Fas and p55-TNFR could be mutated in UK110 cells. To clarify the genetic phenotype of UK110 cells, we performed somatic cell hybridization with parental U937 and the UK110 cells. All of the hybrid clones were as sensitive as the parental U937 cells to apoptosis by both anti-Fas and anti-p55-TNFR antibodies, indicating that the apoptosis resistance in UK110 cells resulted from recessive genotype.

Antibodies↗

PubMed1994

Expression and function of multidrug resistance P-glycoprotein in a cultured natural killer cell-rich population revealed by MRK16 monoclonal antibody and AHC-52.

Natural killer (NK) cells have been reported recently to be the highest in expressing multidrug resistance (MDR) P-glycoprotein among normal mature lymphoid cells. Using a cultured NK cell-rich population, we have examined the expression and function of P-glycoprotein, in particular its role in NK cell-mediated cytotoxicity, by employing two MDR-reversing agents (nicardipine and AHC-52, a nicardipine analog almost devoid of calcium channel blocking activity) and monoclonal antibody against P-glycoprotein (MRK-16). The expression of P-glycoprotein was detected by flow cytometry and polymerase chain reaction of reverse transcribed mRNA. P-glycoprotein was functional in terms of rhodamine dye excretion and its susceptibility to the MDR-reversing agents. Since the concentration of nicardipine required for 50% inhibition (IC50) of rhodamine dye excretion (2 microM) was close to that of AHC-52 (5 microM), it was suggested that their inhibitory effects were not due to calcium channel blocking activity, and that ACH-52 is a selective inhibitor for P-glycoprotein. The IC50 of nicardipine for NK cell-mediated cytotoxicity (33 microM) was also close to that of AHC-52 (26 microM), indicating that P-glycoprotein is involved in NK cell-mediated cytotoxicity. In support of this, MRK16 inhibited NK cell-mediated cytotoxicity in a concentration-dependent manner. Both binding of target cells to NK cells and post-binding events were affected by AHC-52, suggesting that P-glycoprotein is involved in several steps in NK cell-mediated cytotoxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Expression of insulin receptor substrate-1 in hepatocytes: an investigation using monoclonal antibodies.

To investigate the expression and subcellular distribution of insulin receptor substrate-1 in hepatocytes, which are major targets of insulin along with muscle and adipose tissue, we obtained monoclonal antibodies by immunizing mice with a fusion protein consisting of the C-terminal portion of the human insulin receptor substrate-1 and glutathione-S-transferase. Two of the monoclonal antibodies (designated as 7B3 and 6G5) were found to be useful for immunohistochemical studies. Using 6G5 we demonstrate a high level of expression of insulin receptor substrate-1 in liver cirrhosis hepatocytes and variable expression in hepatocellular carcinoma cells. These results suggest that insulin receptor substrate-1 may play a role in liver regeneration during cirrhosis and that an insulin signaling cascade may be involved in hepatocarcinogenesis.

Animals↗

PubMed1994

Human recombinant interferons-beta and -gamma decrease gelatinase production and invasion by human KG-2 renal-carcinoma cells.

We investigated the effects of human recombinant interferons (r-IFNs) on gelatinase production and invasion by human renal-cell carcinoma (HRCC). Incubation of KG-2 HRCC with human r-IFN-beta or -gamma (but not -alpha) suppressed transcription of the 72-kDa gelatinase gene and, hence, production of gelatinase activity. These inhibitory effects of interferons (IFNs) were independent of their antiproliferative effects. Treatment of KG-2 cell with r-IFN-beta or -gamma significantly inhibited cell invasion through reconstituted basement membrane toward chemoattractants produced by kidney fibroblasts. The inhibitory activity of r-IFNs was specific to the KG-2 cells since gelatinase activity by various fibroblasts was unaffected. These findings suggest that r-IFN-beta or IFN-gamma may be used to inhibit the invasive potential of HRCC.

Carcinoma, Renal Cell↗

PubMed1994

Transport of cyclosporin A across the brain capillary endothelial cell monolayer by P-glycoprotein.

P-glycoprotein, a multidrug transporter protein, exists in the brain capillary endothelium. To study the function of P-glycoprotein in brain capillary endothelium as a barrier against cyclosporin A, we examined the interaction of cyclosporin A with P-glycoprotein expressed in cultured brain capillary endothelial cells (MBEC4). P-glycoprotein of MBEC4 specifically bound [125I]iodoaryl azidoprazosin, and the binding was inhibited by cyclosporin A and vincristine. Intracellular accumulation of cyclosporin A in MBEC4 was about one-third the amount accumulated in mouse aortic endothelial cells (MAEC3), a cell line that did not express P-glycoprotein. The reduced accumulation of cyclosporin A in MBEC4 was increased by verapamil, a competitive inhibitor of transport function of P-glycoprotein. Cyclosporin A was preferentially transported from basal to apical side when the cell monolayer of MBEC4 was formed; however this transendothelial transport was not observed across cell monolayer of MAEC3. Verapamil inhibited the transendothelial transport of cyclosporin A across the MBEC4 monolayer. Thus P-glycoprotein in brain capillary endothelium could transport cyclosporin A across the endothelium from the basal to the apical side. These observations suggest that P-glycoprotein is involved in the complex function of the blood-brain barrier as a secretory detoxifying transporter of cyclosporin A.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Comparative evaluation of S9788, verapamil, and cyclosporine A in K562 human leukemia cell lines and in P-glycoprotein-expressing samples from patients with hematologic malignancies.

The activity of S9788, recently synthetized as a modulator of multidrug resistance (MDR), was compared with verapamil and cyclosporine A in normal sensitive and MDR K562 cell lines, then in samples from 33 patients with hematological malignancies, using flow cytometry with simultaneous detection of P-glycoprotein and determination of intracellular daunorubicin fluorescence. This technique was compared and correlated with a tritiated daunorubicin accumulation method. In K562 cell lines, S9788 exhibited a significantly higher reversing activity than verapamil and cyclosporine A, and allowed a complete restoration of the accumulation of daunorubicin when used at 5 mumol/L. In the clinical samples, the three compounds were evaluated at equimolar concentration (5 mumol/L) using concomitant exposure to daunorubicin and to the reversing agent. In P-glycoprotein-negative samples, no significant effect on intracellular daunorubicin fluorescence of any of the reversing agents was noted. In the 15 P-glycoprotein-positive samples, a significant increase in daunorubicin fluorescence, by at least one reversing agent, was seen in 10 cases, among which S9788 reversing activity was higher than that of the two other agents in seven cases. Complete reversal was only achieved in one case with S9788.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

MDR1 gene expression: its effect on drug resistance to doxorubicin in human hepatocellular carcinoma cell lines.

BACKGROUND: Hepatic tumors are resistant to many chemotherapeutic agents. Although elevated MDR1 (also known as PGY1) gene expression has been shown in such tumors, no direct association has been established between the gene expression and multidrug resistance. PURPOSE: To evaluate the role of the MDR1 gene in the drug resistance of hepatoma, we tested nine human hepatoma cell lines for their expression of the MDR1 gene. METHODS: We measured the MDR1 messenger RNA (mRNA) expression by RNA slot-blot analysis and by immunocytochemical staining with a P-glycoprotein-specific monoclonal antibody, MRK16. The in vitro chemosensitivity of these cell lines to fluorouracil, doxorubicin, mitomycin C, cisplatin, and etoposide (VP-16) was determined using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) colorimetric assay. For doxorubicin cytotoxicity, we also tested the potentiating effect of several multidrug resistance-reversing agents. RESULTS: Slot-blot analysis and immunocytochemistry showed that two cell lines expressed high levels of MDR1 mRNA, one expressed an intermediate level, and all others were low expressors. The MTT assay results showed that all cell lines tested were generally resistant to chemotherapeutic agents. The assay area under the curve (AUC) was within a clinically achievable range only for VP-16 in one of nine cell lines. When the IC50 values were compared among the cell lines, the results revealed a close association with the MDR1 gene expression only for doxorubicin resistance. Verapamil and quinidine lowered the IC50 values of doxorubicin for MDR1-positive cell lines. The lowered assay AUC levels for both reversing agents, however, were still higher than the clinically achievable range. CONCLUSION: These results indicate that the MDR1 gene probably has a role in doxorubicin resistance in hepatocellular carcinoma and that the resistance can be overcome by some multidrug resistance-reversing agents. IMPLICATIONS: Some widely used anticancer agents might be ineffective for treating hepatocellular carcinoma in clinical situations even when combined with reversing agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Nonenzymatic reductive activation of 7-N-((2-([2-(gamma-L-glutamylamino)ethyl]dithio)ethyl))mitomycin C by thiol molecules: a novel mitomycin C derivative effective on mitomycin C-resistant tumor cells.

7-N-((2-([2-(gamma-L-Glutamylamino)ethyl]dithio)ethyl))mitomycin C (KW-2149) is an analogue of mitomycin C (MMC) and has prominent activities against various tumors. We studied the antitumor effects of KW-2149 in MMC-resistant variants of human colon carcinoma HT-29 (HT-29/MMC) and mouse hepatoma Hepa-I (C4, B13NBii1) cells, which are deficient in DT-diaphorase and cytochrome P450 reductase, respectively. These enzymes mediate the reductive activation of MMC in the cells. Although HT-29/MMC and C4, B13NBii1 cells showed significant resistance to MMC, they showed sensitivity tl KW-2149 comparable to their parental tumors, indicating that DT-diaphorase and cytochrome P450 reductase could not be involved in the activation of KW-2149. In studying the activation mechanism of KW-2149, we found that glutathione (GSH) and cysteine significantly enhanced the cytotoxicity of KW-2149 in HT-29 cells. The DNA adduct of KW-2149 was increased when HT-29 cells or the isolated nuclei of the cells were incubated with KW-2149 in the presence of physiological concentrations of GSH and cysteine. KW-2149 alkylated calf thymus DNA in the presence of GSH and cysteine in vitro. These results indicate that activation of KW-2149 by thiol molecules, unlike MMC, could be an important activation mechanism of KW-2149 to form DNA adduct and to exert its cytotoxicity. This is the reason why KW-2149 is effective against MMC-resistant tumors with deficiencies in the MMC activation enzymes.

Buthionine Sulfoximine↗

PubMed1994

Mycobacterium tuberculosis induces expression of P-glycoprotein in promonocytic U1 cells chronically infected with HIV type 1.

A productive infection with HIV-1 is associated with an increased expression of a 170 kd plasma membrane P-glycoprotein (P-gp), that functions as a metabolically active drug efflux pump, in human T and macrophage cell lines. In this investigation we show that phagocytosis of M. tuberculosis by U1 cells, that are chronically infected with HIV-1 but produce minimal or no virus, resulted in an expression of P-gp that was associated with increased production of HIV-1 p24 antigen. In addition, U1 cells that had phagocytosed M. tuberculosis accumulated significantly less intracellular isoniazid (INH) as compared to U1 cells. Furthermore, verapamil, that binds to P-gp, increased the intracellular accumulation of INH and the sensitivity of M. tuberculosis to INH. These data suggest induction of P-gp expression may be one of the host mechanisms for the development of multidrug resistant M. tuberculosis in HIV 1 infection.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Inhibitory effects of tumor invasion-inhibiting factor 2 and its conjugate on disseminating tumor cells.

Tumor invasion-inhibiting factor 2 (IIF-2) is a polypeptide of 21 amino acids which binds to the surface of tumor cells and inhibits experimental invasion in vitro. An albumin conjugate of IIF-2 was used to examine its potential as an antimetastatic compound. The conjugate inhibits in vivo lung metastasis of various highly metastatic tumor cells, including murine melanoma, colon adenocarcinoma, squamous cell carcinoma, forestomach carcinoma, and human fibrosarcoma. In addition to the anti-lung metastasis activity of this compound, it also showed the inhibitory effects on liver and spleen metastasis of murine T-lymphoma cells. A single administration of the conjugate with melanoma cells resulted in prolonged survival times, and their lung colonization was also inhibited when the conjugate was administrated i.v. at times ranging from 6 h before to 1 h after tumor cell inoculation. Similarly, i.p. administration 1 h prior to melanoma cell injection suppressed lung colonization. Pharmacokinetic analysis revealed that the conjugate was more stable than IIF-2 peptide alone. Approximately 10% of the conjugate remained circulating 2 h postinjection and persisted 20 h without degradation, compared with rapid clearing of the unconjugated IIF-2 peptide within 5 min. Furthermore, spontaneous lung metastasis of murine melanoma and colon adenocarcinoma cell was inhibited by successive i.p. administration of the conjugate before the removal of the primary site, with no effect on primary tumor growth. The conjugate significantly reduced tumor cell arrest in the lung and both the IIF-2 peptide and its conjugate demonstrated potent inhibition of basal as well as cytokine-induced-stimulated tumor cell motility. These results suggest that one mode of IIF-2 action may be inhibition of the extravasation of metastasizing cells which have arrested in a target organ, and that the IIF-2-albumin conjugate may be a potent antimetastatic substance with utility in the prevention of artificial seeding of tumor cells during surgical removal of the primary lesions as well as inhibiting metastasis from established metastases.

Albumins↗

PubMed1994

Improved flow-cytometric detection of low P-glycoprotein expression in leukaemic blasts by histogram subtraction analysis.

Expression of the drug efflux pump P-glycoprotein (PGP) was determined by flow cytometry in human lung cancer cell lines and in leukaemic blasts derived from 60 patients with acute myeloid leukaemia (AML). Cells from the PGP-negative parent cell line H69/P and the multidrug resistant (MDR)-variant H69/LX4 could be clearly distinguished by immunostaining with the anti-PGP monoclonal antibody MRK16. In leukaemic blasts, the differences in fluorescence intensities between samples incubated with the idiotypic nonspecific (control sample) and specific antibody (test sample) were small, resulting in nondisjunct distributions. Only in a few leukaemia specimens were PGP-expressing cells detectable by simple subtraction of histograms using a threshold. Therefore, an improved histogram subtraction analysis, based on curve fitting and a statistical test, was applied to distinguish antigen-positive from antigen-negative cells. Moreover, a multiparametric staining procedure employing propidium iodide (PI) and Hoechst 33342 was used to reduce staining artefacts. By this approach, leukaemic cells with low expression of PGP were detected in 39 out of 60 cases. Subpopulations with strong PGP expression, resulting in disjunct fluorescence distributions, were not observed. Only in 5 out of 60 specimens were PGP expressing cells detected by a conventional subtraction of histograms using a threshold. Comparison of data obtained with or without the multiparametric gating procedure indicated that the increase in sensitivity was mainly due to the application of the data analysis. However, exclusion of cell debris using PI and Hoechst staining properties reduced the deviation of data from mean values. No relation between PGP expression and cell cycle position was observed in either cell lines or in leukaemic blasts.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Resistance to antitumor agent-induced apoptosis in a mutant of human myeloid leukemia U937 cells.

Human monocytic leukemia U937 cells underwent apoptosis when the cells were treated with a variety of antitumor drugs. We isolated and characterized a mutant, UK711, that was resistant to apoptosis induced by antitumor agents. When U937 cells were treated with etoposide (VP-16), an inhibitor of DNA topoisomerase II, apoptosis occurred in a large number of cells, and flow-cytometric analysis revealed that the majority of cells in S phase underwent apoptosis within 2 h of the end of treatment. Such treatment, however, induced apoptosis in only a few UK711 cells. The levels of protein-DNA covalent links and DNA double-strand breaks caused by VP-16 were similar in both cell lines, indicating that the initial DNA damage caused by VP-16 were comparable, whereas the following cellular responses that resulted in apoptosis differed between these cell lines. UK711 cells also showed resistance to apoptosis induced by such antitumor agents as 1-(beta-D-arabinofuranosyl) cytosine (Ara-C), adriamycin, mitomycin C, camptothecin, and by cytotoxic stimuli such as staurosporine, cycloheximide, and uv irradiation. UK711 cells, however, were sensitive to apoptosis induced by tumor necrosis factor (TNF), as were U937 cells. In accordance with resistance to apoptosis induced by antitumor agents, UK711 cells showed significant actual drug resistance to these antitumor agents. The present results indicate that UK711 cells acquired resistance to apoptosis induced by a variety of cytotoxic stimuli resulting in actual anticancer drug resistance. This cell line may be useful in studying the mechanism of apoptosis induced by cytotoxic agents.

Antineoplastic Agents↗

PubMed1994

Ultrastructural localization of P-glycoprotein on capillary endothelial cells in human gliomas.

The P-glycoprotein (P-Gp) encoded by the human multidrug-resistance gene MDR1 has been suggested to play certain roles in the blood-brain barrier (BBB). However, the detailed mechanism of the activity of P-Gp in multidrug-resistance (MDR) remains unclear in human glioma. We examined the localization of P-Gp in human glioma by immunohistochemical (IHC) and immunoelectron microscopic (IEM) methods with anti P-Gp monoclonal antibodies (C219, MRK16). We also examined MDR1 expression in primary glioma and xenografts by reverse transcription-polymerase chain reaction (RT-PCR) with human MDR1-specific primers. The IHC study showed no P-Gp expression on tumour cells but it was present on capillary endothelial cells and IEM analysis showed definitive localization on their luminal surface. MDR1 gene expression was detected in eight primary glioma and three normal brain specimens by RT-PCR, but not in glioma xenografts. The lack of MDR1 expression in these cells appears to be a consequence of the replacement of the original human stroma, including blood vessels, by murine stroma in glioma xenografts. The unique distribution of P-Gp on the capillary blood vessels was confirmed in human glioma by the results of immunohistochemical and molecular biological studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Antitumor effects of IST-622, a novel synthetic derivative of chartreusin, against murine and human tumor lines following oral administration.

The antitumor effects of 6-O-(3-ethoxypropionyl)-3',4'-O-exo- benzylidenechartreusin (IST-622), a new synthetic derivative of chartreusin (CT), were investigated. Following oral administration, IST-622 showed marked antitumor effects against various mouse tumors such as P388 and L1210 leukemias, B16 melanoma, Lewis lung carcinoma, Colon 26 and Colon 38 adenocarcinomas, and M5076 reticulum-cell sarcoma. The best antitumor effects were obtained by five intermittent treatments given every 4 days. In addition, IST-622 showed a significant growth-inhibitory effect against two human tumor xenografts, a large-cell lung cancer (Lu-116) and a gastric adenocarcinoma (St-4), among the seven lines tested. IST-622, which was rapidly metabolized into 3',4'-O-exo-benzylidenechartreusin (A-132) and not into CT in vivo or in culture medium, exhibited remarkable growth-inhibitory activity against P388 leukemia in vitro, its 50% growth-inhibitory concentration (IC50) being over 20-fold lower than that of CT. IST-622 showed an in vivo antitumor effect superior to that of authentic A-132, possibly resulting from a higher absorption ratio of IST-622 through the gastrointestinal tract. IST-622 is now under clinical phase I study in Japan.

Administration, Oral↗

PubMed1994

Characterization of newly established adriamycin resistant human leukemic cell lines (KY-ADR1 and KY-ADR2).

New adriamycin (ADR) resistant human leukemic cell lines (KY-ADR1 and KY-ADR2) have been established. KY-ADR1 was selected from a cytosine arabinoside (Ara C) resistant cell line by gradually increasing the concentration of ADR and KY-ADR2 from the parental cell line, KY-821, by the same method. The IC50s of both cell lines were 4.3 x 10(-5) and 3.6 x 10(-5) M ADR, respectively. Both lines revealed a similar cross resistance to various anticancer drugs, but KY-ADR1 was resistant to Ara C, whereas KY-ADR2 was sensitive. MDR1 gene was over-expressed and P-glycoprotein was expressed on the cytoplasmic membrane in both lines. Neither verapamil nor cyclosporin A could completely reverse ADR resistance. In addition, no significant changes in topoisomerase II and glutathione-s-transferase levels were detected. These findings indicate that ADR resistance in both cell lines is mainly mediated by P-glycoprotein and some other mechanism may be present. Interestingly, growth of both cell lines was stimulated by natural IL-1 and not affected by TNF alpha and IFN gamma, whereas growth of parental KY-821 was inhibited by these factors. These cell lines will provide new biological aspects on drug resistant leukemic cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by daphnodorins.

Three flavans, daphnodorins A, B and C isolated from Dahpne odora THUNB. were tested for their abilities to inhibit human immunodeficiency virus type 1 (HIV-1(IIIB)) replication in MT-4 cells. The effective concentrations (EC50) of daphnodorins A, B and C against HIV-1-induced cytolysis were 0.26 +/- 0.08, 1.8 +/- 0.6 and 3.6 +/- 0.5 micrograms/ml, respectively. Also these three compounds showed inhibitory effects of p24 antigen in human peripheral blood lymphocytes. As compared with 2',3'-dideoxycytidine 5'-triphosphate (DDC-TP), daphnodorin A and daphnodorin C had relatively weak inhibitory effects on the reverse transcriptase of HIV-1, while daphnodorin B did not show any inhibitory effect at concentrations up to 1000 micrograms/ml. These three compounds showed marked inhibitory effects on syncytium formation between HIV-1(IIIB)-infected and uninfected MOLT-4 (clone 8) cells at 3-30 micrograms/ml without inducing cytotoxicity. The concentrations of the compounds blocking syncytium formation were consistent with the effective concentrations (EC50) against HIV-induced cytolysis of MT-4 cells. These results, differing from reverse transcriptase inhibitors, suggest that the daphnodorins exert their anti-HIV-1 activity through inhibition of early events of viral replication including adsorption of the virions to the cells or the subsequent entry.

Antiviral Agents↗

PubMed1994

Evaluation of antitumor activity of navelbine (vinorelbine ditartrate) against human breast carcinoma xenografts based on its pharmacokinetics in nude mice.

The in vitro antitumor activity of navelbine (NVB, KW-2307), a newly synthesized vinca alkaloid, was compared with that of adriamycin (ADM) against human breast carcinomas inoculated into nude mice at the maximum tolerated dose (MTD) and clinically equivalent dose (CED). The plasma levels of NVB after intravenous injection into nude mice at doses of 1.2 and 4.8 mg/kg diminished rapidly during the early phase (0-1 h), followed by a very long shallow one. NVB was still detected 96 h after administration at a dose of 4.8 mg/kg. The pharmacokinetic parameters of NVB in plasma indicated that NVB extensively distributes to tissues. The CED of NVB was provisionally decided to be 4.8 mg/kg based on the comparison of AUC values at 24-infinity h between human patients and nude mice. When compared by a single injection of MTD (NVB, 16 mg/kg; ADM 12 mg/kg), NVB was effective against all four tumor lines, MC-2, MC-8, MMKY and H-31, while ADM was effective only against H-31. On the other hand, the body weight loss by NVB was mild as compared with that by ADM, indicating that the antitumor activity of NVB is superior to that of ADM at their MTDs. A single injection of NVB at its CED (4.8 mg/kg) produced a poor antitumor effect and no or little toxicity in terms of body weight loss, as compared with those at MTD. However, when NVB was administered intermittently at CED, it exhibited significant antitumor activity against three tumor lines. The body weight loss was still mild even on this intermittent schedule.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma, Papillary↗