Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the tissue distribution, toxicity, and antitumor activity of anthracyclines encapsulated in hydrogenated phosphatidylinositol (HPI)-containing liposomes which show a characteristic long circulation time in plasma (J. Natl. Cancer Inst., 81: 1484-1488, 1989). Phosphatidylglycerol (PG)-containing liposomes were used for comparison. Doxorubicin (DOX) or epirubicin (EPI) was encapsulated in the aqueous interior of small (65-100 nm mean diameter) HPI or PG liposomes. The DOX and EPI levels in i.m. tumor implants of the J6456 lymphoma were significantly raised by delivery in HPI liposomes but not by delivery in PG liposomes. No such increase was observed in normal muscle tissue. When DOX encapsulated in HPI liposomes was injected i.v. into BALB/c mice bearing an ascitic form of the J6456 lymphoma, more than 10% of the injected dose was recovered in the ascitic fluid in liposome-associated form. No significant accumulation of liposomal drug was observed in peritoneal washes from tumor-free mice. DOX encapsulation in either PG- or HPI-containing liposomes reduced the lethal toxicity of the drug in mice. However, only the HPI-DOX formulation was significantly more active than free DOX in the treatment of the ascitic J6456 tumor at all dose levels tested. Therapeutic results with EPI encapsulated in HPI liposomes also showed an efficacy superior to that of free EPI. These studies provide evidence that anthracyclines delivered in long-circulating liposomes extravasate with relative selectivity in tumor areas, improving the overall therapeutic index.
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PMID:Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes. 173 51

Three model systems involving LOX human malignant melanoma cells in nude rats were used to compare the chemosensitivity of tumors growing in different tissues. Groups of 4-18 rats with either s.c. xenografts, lung tumor colonies, or bone metastases were treated with cisplatin, doxorubicin, dacarbazine, or mitozolomide. The antitumor effect in the s.c. model was expressed as specific growth delay, and in the experimental metastasis studies as relative increase in life span (RILS), calculated on the basis of observed disease-free survival. Cisplatin had a moderate but significant effect on the progression of LOX tumor growth in all three systems. Doxorubicin was clearly more efficacious, but for both drugs tumor-free survivors were rare or absent. Importantly, for each of the compounds the levels of response were roughly the same in all three models, with specific growth delay and RILS values in the range of 0.2-0.3 for cisplatin and 0.5-0.9 for doxorubicin. In contrast, a significant site-dependent difference in sensitivity of the LOX tumors was observed for two alkylating agents. Thus, dacarbazine, which temporarily caused complete regression of s.c. xenografts (specific growth delay = 21.0), showed a moderate activity in the lung tumor model (RILS = 1.0) but had only a limited effect (RILS = 0.4) on bone metastases. Mitozolomide gave a curative effect in 6 of 10 animals with s.c. and in 4 of 4 animals with lung tumors, whereas in the bone metastasis model it was only slightly superior to doxorubicin (RILS = 1.1). In preliminary attempts to elucidate the underlying mechanisms, no site-dependent differences in drug distribution and in two cellular detoxifying systems were detected. The data demonstrate the usefulness of the LOX models for studying the clinically relevant problem of site-dependent tumor response to chemotherapy.
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PMID:Site-dependent differences in sensitivity of LOX human melanoma tumors in nude rats to dacarbazine and mitozolomide, but not to doxorubicin and cisplatin. 173 96

Doxorubicin (DOX) is a potent anticancer agent, the use of which is limited by its cumulative dose-dependent cardiotoxicity. Pentoxifylline (PTX) is a non-toxic methylxanthine used clinically for the treatment of intermittent claudication. It is an active haemorheological agent, used for the treatment of defective microcirculation. In the present study, we employed PTX as a drug response modulator in combination with DOX to achieve increased cytotoxicity in human chronic myeloid leukemia (CML) cells. Inhibition of 3H-TdR incorporation was used as a measure of cytotoxicity. PTX at 100 microM concentration significantly (P less than 0.001) potentiated DOX-mediated DNA biosynthesis inhibition in CML cells in vitro. Significant synergistic inhibition was seen in 13 out of 22 CML samples. Decreased DOX accumulation is a characteristic feature of DOX resistant tumor cell lines. Drug accumulation studies demonstrated that PTX significantly (P less than 0.02) increased the intracellular accumulation of DOX in the CML cells. The enhanced DOX accumulation can be a mechanism of increased cytotoxicity by DOX-PTX combination.
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PMID:Amelioration of doxorubicin resistance by pentoxifylline in human chronic myeloid leukemia cells in vitro. 177 Dec 98

Doxorubicin (DOX) and doxorubicinol (DOXOL) were analyzed by high performance liquid chromatography in serum, bile and urine in a lymphoma patient with tumor-induced biliary obstruction. The patient had an indwelling T-tube and was given DOX containing combination chemotherapy. The bile was collected via the T-tube and given orally (together with beer) to the patient four times daily. New samples were obtained three weeks later when normal bile flow was re-established. The serum and bile concentration curves for DOX and DOXOL show great similarity between the first and second chemotherapy course, respectively. This finding strongly argues against an enterohepatic circulation of DOX or DOXOL of clinical importance in man.
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PMID:No evidence of enterohepatic circulation of doxorubicin in a patient with transitory biliary obstruction due to lymphoblastic lymphoma. 177 62

A rapid, simple chemosensitivity assay, assessing tumor cell nuclear uptake of doxorubicin hydrochloride, was evaluated in 16 dogs with appendicular osteosarcoma. Doxorubicin was administered to dogs in 5 biweekly treatments, and surgical resection was performed after the second or third treatment. The chemosensitivity assay was performed on biopsy specimens from all dogs before chemotherapy. It was repeated on tissue from resected tumors, and tumors were evaluated histologically to determine the degree of necrosis resulting from chemotherapy. Disease-free and total survival time correlated significantly (P less than 0.05 in both cases) with the degree of postchemotherapy necrosis of the primary tumors. Significant correlation was not apparent between the percentage of tumor cells with nuclear uptake of doxorubicin (in either biopsy or resection samples) and disease-free or total survival time. The percentage of cells with nuclear uptake of doxorubicin in surgically resected tumors correlated significantly (P less than 0.05) with percentage of necrosis.
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PMID:In vitro assay of nuclear uptake of doxorubicin hydrochloride in osteosarcoma cells of dogs. 178 8

Vitamin K3 was employed as a resistance-modifying agent to investigate its activity in enhancing mitoxantrone (MITO)-induced cytotoxicity in parental (P388/S) and multidrug resistant (P388/ADR) P388 leukemia cells. Vitamin K3 potentiated the antitumor effects of MITO in P388/S and P388/ADR tumor cells as monitored by inhibition of tumor cell survival (MTT assay). MITO and vitamin K3 in combination effected an enhanced inhibition of [3H]thymidine (DNA synthesis) and [3H]uridine (RNA synthesis) and also increased the life span of the sensitive and resistant tumor-bearing animals. The effect of vitamin K3 on the induction of DNA strand breaks by MITO was also examined. Increased fragmentation of DNA was illustrated in the sensitive and resistant P388 leukemia cells exposed to the combination. Observations indicate the restoration of sensitivity in P388/ADR cells to MITO by vitamin K3 that may be due to its ability to increase the MITO-induced DNA strand breaks.
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PMID:Antiproliferative effects of mitoxantrone in ADR-sensitive and ADR-resistant P388 leukemia cells enhanced by vitamin K3. 180 14

Using periodate oxidation method adriamycin was linked to monoclonal antibody OC859, and a monoclonal antibody-adriamycin (McAb ADR) conjugate was produced. The molar ratio of ADR:OC859 was 12:1. This drug-antibody conjugate still retained its cytotoxic effects and antibody activities. The cytotoxic effects of McAb-ADR conjugate on the growth of tumor cells CAOV3 was determined by microculture tetrazolium assay. It revealed that when the concentration of the McAb-ADR conjugate was 1 microM more than 50% of CAOV3 cells were inhibited. And for normal endometrial cells no more than 50% inhibition could be shown even with the concentration up to 10 microM. In vivo, the human ovarian epithelial carcinoma transplanted to nude mice was also inhibited with McAb-ADR conjugate. The above results showed that the McAb-ADR conjugate can selectively cause inhibition of tumor cells both in vivo and in vitro, and may be helpful in the treatment of ovarian epithelial carcinoma in the future.
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PMID:[Production of adriamycin covalent binding to monoclonal antibody OC-859 and its anti-tumor activities]. 180 4

Several mechanisms of drug resistance have been defined using cell lines selected for resistance in vitro. However, the relevance of these to tumor cell resistance in vivo remains unclear. We established tumor cell lines from biopsies of human sarcomas before and after doxorubicin therapy. One pretreatment sarcoma line, STSAR90, was 6-fold less sensitive to doxorubicin than was a normal fibroblast line, AG1522. The sensitivities of six other sarcoma lines were similar to that of AG1522. STSAR90 cells did not overexpress P-glycoprotein mRNA, by Northern analysis with the pCHP1 complementary DNA fragment. Photoaffinity labeling with the vinblastine analogue N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine did not show increased P-glycoprotein concentrations. Accumulation of [3H]daunomycin was not decreased in STSAR90 compared with a less resistant sarcoma line, STSAR11, nor was the doxorubicin sensitivity of STSAR90 increased by coincubation with verapamil. Glutathione levels were twice as high in STSAR90 as in STSAR11, and glutathione peroxidase activity was 3.5- to 6-fold higher. This was due mostly to an increase in selenium-dependent peroxidase activity. After exposure to doxorubicin, STSAR90 cells formed only half as much measurable hydroxyl radical as STSAR11, as detected by electron spin resonance spectrometry. Doxorubicin sensitivity was increased in STSAR90 cells when intracellular glutathione levels were reduced by buthionine sulfoximine. These results indicate that multidrug resistance due to P-glycoprotein-mediated drug efflux is not the only mechanism of doxorubicin resistance that occurs in sarcomas and that glutathione peroxidase-dependent detoxification of doxorubicin-induced oxygen radicals may contribute to clinical doxorubicin resistance.
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PMID:Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance. 184 55

The effects of the anti-cancer anthracyclines doxorubicin and daunorubicin on the activity of protein kinase C (PKC) were examined in intact Swiss 3T3 cells. The 2 drugs stimulated the phosphorylation of an 80K phosphoprotein found to be identical to that generated in response to the PKC activator 12-O-tetradecanoylphorbol-13-acetate as indicated by gel electrophoresis and peptide mapping. The effect of doxorubicin was dose-dependent in the range 10(-5) to 10(-3) M and was not associated with a detectable translocation of PKC activity from cytosol to the cell membrane. Doxorubicin and daunorubicin were found to increase the incorporation of phosphate into phosphatidic acid, phosphatidylinositol 4-monophosphate and phosphatidyl inositol 4,5-bisphosphate. In addition, the anthracyclines induced a rise in inositol phosphates, thus indicating a stimulation of the breakdown of phosphoinositides. These data are consistent with an indirect mechanism of PKC activation by anthracyclines. We propose that diacylglycerol, which is derived from the hydrolysis of phospholipids, (including the phosphoinositides), by activation of phospholipases, could mediate PKC activation. The described effects, involving cell-signal-transducing pathways, emphasize a new aspect of the cellular actions of these anti-tumor agents.
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PMID:Protein kinase C activation by anthracyclines in Swiss 3T3 cells. 184 61

Rapid advances in the understanding of Wilms' tumor (WT) and its management are being made both in the laboratory and the clinic. Molecular genetic research has implicated loss of a tumor suppressor gene on the short arm of chromosome 11 as one of the pathways responsible for the development of the neoplasm. Preconception maternal (hair dyes) and paternal (occupation) exposures to environmental agents have been the subject of epidemiologic studies of possible risk factors. Histopathologic analyses have identified several different and less common tumor types among those previously aggregated under the WT rubric. WT itself has been subdivided into the so-called favorable histology (FH) and anaplastic forms, the prognosis being worse for the latter. Clinical research has standardized management by surgery, chemotherapy, and radiation therapy (RT) and furthered the identification of risk factors. Patients can now be stratified according to tumor type and stage, and the intensity of treatment modulated accordingly; eg, RT at low doses is used in only 25% of National Wilms' Tumor Study (NWTS) patients without distant metastases. Before the NWTS, it had been given to almost all and at higher doses. Chemotherapy, whether given pre- or postoperatively, is based on dactinomycin and vincristine with Adriamycin [( ADR] doxorubicin; Adria Laboratories, Columbus, OH) added for high-risk patients. The currently used NWTS combined modality therapy for WT patients has dramatically improved survival rates; 95% now are alive 2 years after treatment. Remaining questions are the identification of the late effects of the treatments used and the further refinement of therapy to reduce iatrogenic complications to a minimum.
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PMID:Wilms' tumor: status report, 1990. By the National Wilms' Tumor Study Committee. 184 87


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