Selective cancer therapeutics最新文献_第2页

The uptake and efflux of doxorubicin by a sensitive human bladder cancer cell line and its doxorubicin-resistant subline. 人膀胱癌敏感细胞系及其耐阿霉素亚群对阿霉素的摄取和排出。

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.139

J I Usansky, M Liebert, G Wedemeyer, H B Grossman, J G Wagner

{"title":"The uptake and efflux of doxorubicin by a sensitive human bladder cancer cell line and its doxorubicin-resistant subline.","authors":"J I Usansky, M Liebert, G Wedemeyer, H B Grossman, J G Wagner","doi":"10.1089/sct.1991.7.139","DOIUrl":"https://doi.org/10.1089/sct.1991.7.139","url":null,"abstract":"The uptake and efflux of doxorubicin (Dox) were investigated in a human bladder cancer cell line (UM-UC-6) and in a multi-drug resistant (mdr) subline (UM-UC-6Dox). Unlike previous reports, the initial uptake kinetics of Dox, and its accumulation and retention to steady-state were modelled mathematically. Cells were incubated with Dox and the amount of Dox in the cellular and medium phases was measured by a specific HPLC method. When monitored for 1 min from 0.02 microM to 25 microM Dox, the uptake was very rapid but was significantly faster in the resistant cell line. The initial rate of uptake at t = 0 followed Michaelis-Menten kinetics yielding Vmax values (the maximal rate of uptake) of 15.0 +/- 1.7 and 12.9 +/- 1.2 nmol/10(6)/min and Km (rate at Vmax/2) of 25.2 +/- 4.7 and 16.4 +/- 2.9 microM for UM-UC-6 and UM-UC-6Dox, respectively. There was no metabolism of Dox by keto-reduction or reductive hydrolysis. At 1.0 microM the uptake of Dox to steady-state was biexponential but there was no difference in total cellular Dox concentration between the two cell lines at equilibrium. A 3 compartment sequential closed model was fitted yielding significantly different values for the intercompartmental and hybrid rate constants, indicating altered intracellular distribution in resistant cells. Verapamil (10 microM), trifluoperazine (10 microM) or Tween 80 (0.005%) had no effect on the uptake or efflux of Dox. The UM-UC-6Dox line appeared to show atypical mdr characteristics since net drug accumulation was not lowered and classic P-glycoprotein inhibitors were not effective. The primary mechanism of Dox resistance is not enhanced metabolism or lowered intracellular concentrations.","PeriodicalId":21792,"journal":{"name":"Selective cancer therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/sct.1991.7.139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12983731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 10

Tolerance of extended (28 day) continuous infusion of 5-fluorouracil in advanced head and neck cancer. 延长(28天)连续输注5-氟尿嘧啶治疗晚期头颈癌的耐受性。

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.17

S M Grunberg, C Clay, D V Spicer

{"title":"Tolerance of extended (28 day) continuous infusion of 5-fluorouracil in advanced head and neck cancer.","authors":"S M Grunberg, C Clay, D V Spicer","doi":"10.1089/sct.1991.7.17","DOIUrl":"https://doi.org/10.1089/sct.1991.7.17","url":null,"abstract":"Since continuous exposure increases the cytotoxicity of 5-Fluorouracil, this agent is now commonly administered by 4-5 day continuous infusions. However Phase I studies have suggested that infusion of doses up to 450 mg/m2/day for at least 28 days may be possible. In the present study 12 patients with advanced head and neck cancer were treated with continuous infusion 5-Fluorouracil at starting doses of 400-450 mg/m2/day for 28 days followed by a 14 day rest period. Patients received a median of 2.5 cycles over 10 weeks for a median total 5-Fluorouracil dose of 12,700 mg/m2. One patient achieved Partial Response. Significant stomatitis (Grade II or greater) was seen more frequently than predicted from Phase I studies (8/12 patients) and was the most common cause for dose reduction. Diarrhea, emesis, palmar/plantar syndrome and skin rash were also noted. No significant myelosuppression was seen. Extremely large amounts of 5-Fluorouracil can be delivered to head and neck cancer patients by extended infusion. However due to the high frequency of stomatitis in this population, lower starting doses than those used in this study may be required.","PeriodicalId":21792,"journal":{"name":"Selective cancer therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/sct.1991.7.17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12996468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

A pilot clinical and pharmacokinetic study of intracarotid cisplatin and bleomycin. 颈动脉内顺铂和博来霉素的初步临床和药代动力学研究。

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.29

L G Feun, N Savaraj, Y Y Lee, H Landy, J Martinez-Prieto, C Charnsangavej, J D Post, K F Lee, S Wallace, B Bowen

{"title":"A pilot clinical and pharmacokinetic study of intracarotid cisplatin and bleomycin.","authors":"L G Feun, N Savaraj, Y Y Lee, H Landy, J Martinez-Prieto, C Charnsangavej, J D Post, K F Lee, S Wallace, B Bowen","doi":"10.1089/sct.1991.7.29","DOIUrl":"https://doi.org/10.1089/sct.1991.7.29","url":null,"abstract":"Fifteen patients with progressive primary malignant or metastatic brain tumors were treated on a clinical and pharmacokinetic study with intracarotid cisplatin and bleomycin. Toxicity was tolerable and consisted mainly of nausea and vomiting. Neurologic toxicity included focal seizures (1), leukoencephalopathy (1), and motor weakness (1). Five patients had improvement in CT scans and four patients had stabilization of disease. Recommended dosage for future clinical trials are cisplatin 60 mg/m2 and bleomycin 100 units. Pharmacokinetics of intracarotid cisplatin revealed the jugular vein concentration was twice the peripheral vein level at the end of infusion. Cisplatin is a drug which has demonstrated in vitro activity against malignant gliomas (1). Clinical trials with intravenous administration of cisplatin has shown definite, although limited antitumor activity against primary brain tumors (2,3,4) and metastatic brain tumors (5,6). To enhance its antitumor effect, cisplatin has been administered by the intracarotid route (7,8,9). The results appear encouraging, but neurological and ophthalmological toxicity may occur (8). In our initial study with intracarotid cisplatin, 35 patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation +/- chemotherapy were treated. Of 20 evaluable patients with primary tumors, 6 responded to therapy and 5 had stable disease. Five of 10 evaluable patients with brain metastases responded and 2 had stable disease. For responding primary brain tumor patients the median time to progression was 33 weeks. The recommended dose for intracarotid cisplatin was 60-75 mg/m2 administered every 3-4 weeks (7,8). Higher cisplatin doses produced more central neurological toxicity. There is limited data on the central nervous system pharmacology of cisplatin.(ABSTRACT TRUNCATED AT 250 WORDS)","PeriodicalId":21792,"journal":{"name":"Selective cancer therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/sct.1991.7.29","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12881961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Overcoming murine tumor cell resistance to vinblastine by presentation of the drug in multilamellar liposomes consisting of phosphatidylcholine and phosphatidylserine. 用磷脂酰胆碱和磷脂酰丝氨酸组成的多层脂质体给药克服小鼠肿瘤细胞对长春花碱的耐药性。

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.103

C A Seid, I J Fidler, R K Clyne, L E Earnest, D Fan

{"title":"Overcoming murine tumor cell resistance to vinblastine by presentation of the drug in multilamellar liposomes consisting of phosphatidylcholine and phosphatidylserine.","authors":"C A Seid, I J Fidler, R K Clyne, L E Earnest, D Fan","doi":"10.1089/sct.1991.7.103","DOIUrl":"https://doi.org/10.1089/sct.1991.7.103","url":null,"abstract":"We determined whether vinblastine (VLB) encapsulated within multilamellar vesicle-liposomes (MLV) would reverse target cell resistance to the drug exhibited by the UV-2237M murine fibrosarcoma and its Adriamycin (ADR)-selected multidrug resistant (MDR) variants. Resistant fibrosarcoma cells were grown in medium containing 1 and 10 micrograms/ml ADR to yield the MDR lines UV-2237M/ADRR (ADR-1) and UV-2237M/ADRRR (ADR-10), respectively. VLB encapsulated in MLV composed of phosphatidylcholine (PC) and phosphatidylserine (PS) (7:3 molar ratio) was hydrophobic, occupied an internal space equivalent of 6.13 microliters/mumol, and was stable in medium at 37 degrees C for up to 6 days. The 50% inhibitory concentrations (IC50) of VLB were 2, 25, and 70 ng/ml for the parent, ADR-1, and ADR-10 cell lines, respectively. VLB in MLV significantly enhanced sensitivity of tumor cells to VLB. The respective IC50 of liposomal VLB were 0.5, 5.7, and 12 ng/ml for the parent, ADR-1, and ADR-10 lines. MLV containing saline were not toxic to the cells. These data indicate that presentation of VLB entrapped in PC:PS MLV provides a method to overcome tumor cell resistance to this drug.","PeriodicalId":21792,"journal":{"name":"Selective cancer therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/sct.1991.7.103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12934760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Effect of verapamil on the uptake and efflux of etoposide (VP16) in both sensitive and resistant cancer cells. 维拉帕米对敏感和耐药癌细胞中依托泊苷(VP16)摄取和外排的影响

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.75

M R Feng, M Liebert, G Wedemeyer, H B Grossman, W R Mancini, M Williams, J G Wagner

{"title":"Effect of verapamil on the uptake and efflux of etoposide (VP16) in both sensitive and resistant cancer cells.","authors":"M R Feng, M Liebert, G Wedemeyer, H B Grossman, W R Mancini, M Williams, J G Wagner","doi":"10.1089/sct.1991.7.75","DOIUrl":"https://doi.org/10.1089/sct.1991.7.75","url":null,"abstract":"The effect of calcium antagonist verapamil on the uptake and efflux of Etoposide (VP16), a semi-synthetic derivative of podophylotoxin and a broad spectrum antineoplastic agent, has been investigated and compared in sensitive (UM-UC-2) and resistant (UM-UC-9) human bladder cancer cells, and L1210 leukemia cells, by using both radioisotope (3[H]-VP16) liquid scintillation and high performance liquid chromatography assay with electrochemical detection. The uptake of VP16 was rapid in all three cell lines, showing an initial rapid linear phase followed by a second slower phase, but at steady state the ratios of intracellular to extracellular VP16 concentrations were only 0.004-0.006. No significant difference in drug uptake was observed in sensitive UM-UC-2 and resistant UM-UC-9 cells at all concentrations studied. Verapamil at a concentration of 10 microM enhanced the intracellular VP-16 levels in all sensitive and resistant cell lines. The increments were 21.5% for UM-UC-2, 11.8% for UM-UC-9, and 31.0% for L1210 cells after 30 minutes incubation with 1 microM VP16. A slower efflux of VP16 was observed in verapamil treated cells in all three cell lines. There was a small increase in the nonexchangeable components in verapamil treated cells, although only 5-10% of VP16 was retained. No peak other than that of VP16 was detected in the HPLC chromatogram of extracts from both cell pellet and influx or efflux medium.","PeriodicalId":21792,"journal":{"name":"Selective cancer therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/sct.1991.7.75","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12917853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

A multi-modality approach for the treatment of AIDS. 治疗艾滋病的多模式方法。

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.23

M B Yatvin

引用次数: 0

Expression of the multidrug transporter P-glycoprotein and in vitro chemosensitivity: correlation with in vivo response to chemotherapy in acute myeloid leukemia. 多药转运蛋白p -糖蛋白的表达和体外化疗敏感性:与急性髓系白血病体内化疗反应的相关性

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.165

M Chitnis, U Hegde, S Chavan, A Juvekar, S Advani

{"title":"Expression of the multidrug transporter P-glycoprotein and in vitro chemosensitivity: correlation with in vivo response to chemotherapy in acute myeloid leukemia.","authors":"M Chitnis, U Hegde, S Chavan, A Juvekar, S Advani","doi":"10.1089/sct.1991.7.165","DOIUrl":"https://doi.org/10.1089/sct.1991.7.165","url":null,"abstract":"Thirty four patients with acute myeloid leukemia (AML) (30 de novo and 4 relapsed) were evaluated for P-glycoprotein (P-gp) expression, and in vitro chemosensitivity. The P-gp expression was evaluated by immunohistochemical method using JSB-1 monoclonal antibody and the results were visualized by peroxidase-antiperoxidase goat antimouse antibody and the in vitro chemosensitivity was measured by the semiautomated MTT colourimetric assay method. Depending upon the percent cells expressing P-gp and the intensity of P-gp staining, the samples were graded as absent, mild or strong for the relative P-gp expression, which was further correlated with the in vitro chemosensitivity and the clinical response of the tumors. Expression of P-gp was seen in 17 of the 30 de novo AML cases and all four relapse cases. Patients with no P-gp expression showed in vitro chemosensitivity while those with strong P-gp expression were resistant in vitro. Patients with mild P-gp expression showed varied chemosensitivity. P-gp expression correlated with clinical response to chemotherapy. Seven out of 11 patients with no P-gp achieved complete remission (C.R.). The other four died early in induction. Of five patients who expressed strong P-gp, four had resistant disease and the autopsy study of the remaining patient who died in induction revealed persistent disease. Of the 10 de novo AML patients who had mild P-gp expression, five achieved C.R. while one had resistant disease and four died in induction. All the four relapsed AML showed mild P-gp expression.(ABSTRACT TRUNCATED AT 250 WORDS)","PeriodicalId":21792,"journal":{"name":"Selective cancer therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/sct.1991.7.165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12852484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Amelioration of doxorubicin resistance by pentoxifylline in human chronic myeloid leukemia cells in vitro. 己酮可可碱对体外人慢性髓性白血病细胞阿霉素耐药性的改善作用。

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.119

A Viladkar, A Juvekar, M Chitnis, S Advani

{"title":"Amelioration of doxorubicin resistance by pentoxifylline in human chronic myeloid leukemia cells in vitro.","authors":"A Viladkar, A Juvekar, M Chitnis, S Advani","doi":"10.1089/sct.1991.7.119","DOIUrl":"https://doi.org/10.1089/sct.1991.7.119","url":null,"abstract":"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.","PeriodicalId":21792,"journal":{"name":"Selective cancer therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/sct.1991.7.119","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12934762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

A model for mimicking the pharmacokinetics of chemotherapy drugs for evaluation of drug effects in a soft agar colony formation assay system. 一个模拟化疗药物的药代动力学模型，用于评估软琼脂菌落形成分析系统中的药物效应。

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.159

M Malmberg, H K Slocum, Y M Rustum

引用次数: 3

Reduction by norepinephrine of the side effects induced by combined hepatic arterial administration of degradable strach microspheres and adriamycin in rats with a liver adenocarcinoma. 去甲肾上腺素降低肝动脉给药可降解微球和阿霉素对肝腺癌大鼠的副作用。

Selective cancer therapeutics Pub Date : 1991-01-01 DOI: 10.1089/sct.1991.7.93

B Jakobsson, H Teder, G Roos, U Stenram

引用次数: 2