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  • 1
    ISSN: 1573-0646
    Keywords: LY 186641 ; diarylsulfonylurea ; renal cell cancer ; phase II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary LY 186641 is a diarylsulfonylurea with a broad spectrum antitumor activity against both murine and human solid tumors. We report here the results of a phase II trial of LY 186641 in advanced renal cell adenocarcinoma. The drug was administered orally, once daily for 2 weeks, every 21 days at a 700 mg/m2/d dose. Sixteen patients were enrolled in this phase II trial; 12 males, 4 females, with a median age of 58 years. All patients had progressive measurable metastatic disease. The primary tumor was surgically removed in all but one patient. Three patients were previously treated by biologic response modifiers (BRMs). A total of 72 courses were administered. The most common side effects were methemoglobulinemia (MetHgb) and anemia which occurred in 13 and 10 patients respectively. The MetHgb did not exceed 15%, and only 3 patients required blood transfusion for grade 3 (2 patients) and grade 4 (1 patient) anemia. Reversible hepatotoxicity was observed in 3 patients. There were one pathological complete response, seven stable disease and 8 progressive disease.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Investigational new drugs 1 (1983), S. 189-189 
    ISSN: 1573-0646
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Investigational new drugs 1 (1983), S. 195-195 
    ISSN: 1573-0646
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-0646
    Keywords: teniposide ; gastric cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The Southwest Oncology Group conducted a trial of VM-26 (teniposide) in patients with advanced gastric cancer. VM-26 60 mg/m2 IV infusion over 30–45 minutes was given daily for 5 days every 21 days. Twentyone eligible patients with measurable disease and a SWOG performance status of 0–2 were analyzed for response and toxicity. Partial responses were seen in 2 of the 21 eligible patients (9.5%). Median survival was 3.8 months. Severe or life-threatening toxicity was observed in 13/21 (62%) patients. This included two drug related deaths related to neutropenic sepsis and seven other patients with grade 4 granulocytopenia (〈 500/mm3). Liver dysfunction and hypotension were seen less often and were not dose limiting. Although the modest activity seen was comparable to that of VP-16 (etoposide) as a single agent, the hematologic toxicity observed in this trial would likely preclude further trials of VM-26 (teniposide) in advanced gastric cancer.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Investigational new drugs 12 (1994), S. 1-13 
    ISSN: 1573-0646
    Keywords: multidrug resistance ; p-glycoprotein ; chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Resistance to chemotherapy is the single most important reason for treatment failure in cancer patients. Over the past 15 years, we have gained significant insight into one of the mechanisms responsible for this process: multidrug resistance (MDR). Far from being a phenomenon limited to the laboratory, multidrug resistance has been identified in a wide variety of newly diagnosed and recurrent human tumors. A number of compounds can block p-glycoprotein and overcome MDRin vitro andin vivo. Current strategies to block MDR are discussed in this review. Future research in this area will focus on the identification of more selective and potent MDR reversing agents and the development of entirely new approaches to overcoming multidrug resistance such as monoclonal antibodies, immunotoxins, and gene therapy.
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  • 6
    ISSN: 1573-0646
    Keywords: piroxantrone ; soft tissue sarcoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Piroxantrone is an anthrapyrazole compound undergoing phase II testing in a variety of diseases. The anthrapyrazoles are a series of compounds synthesized with the intent of maintaining the broad antitumor activity of anthracyclines, but with lessened cardiac toxicity. The Southwest Oncology Group (SWOG) conducted a phase II trial of piroxantrone in advanced soft tissue sarcoma. Treatment consisted of piroxantrone 150 mg/M2 administered intravenously over 1 hour every 21 days. Twenty-five eligible patients were registered to the trial. Twenty-three patients received treatment and are fully evaluable for response and toxicity. Two partial responses were seen for an overall response rate of 9% (95% confidence limit 1%–28%). Abnormal cardiac ejection fraction occurred in five patients, and fatal congestive heart failure developed in one patient on study. Toxicities other than cardiac were tolerable. Based on the observed response rate and cardiac toxicity, further trials of piroxantrone in the treatment of soft tissue sarcoma do not appear warranted.
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  • 7
    ISSN: 1573-0646
    Keywords: bryostatin-1 ; phorbol ester ; protein kinase C ; carcinoma cell lines ; proliferation ; c-myc oncogene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Bryostatin 1 (Bryo) is a naturally occurring macrocyclic lactone with antineoplastic activity. Like the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) it directly activates the calcium- and phospholipid-dependent protein kinase C (PKC), thus generating a number of different cellular responses. We investigated the effects of Bryo and TPA on DNA synthesis, proliferation, viability and c-myc protooncogene expression of the human carcinoma cell lines COLO-320, MEL-HO, and KB-3-1. TPA inhibited [3H]-thymidine incorporation in all three cell lines in a dose-dependent manner, whereas Bryo only inhibited the DNA synthesis in MEL-HO, but not in KB-3-1 and COLO-320 cells. Within the concentration ranges used, TPA and Bryo were found to have a low toxicity. Counting of the cells confirmed the observed inhibition of cell proliferation. However, the enzymatic conversion of MTT, applied as a colorimetric proliferation assay, was not significantly affected by both biomodulators. Time-course experiments revealed a rapid onset of the inhibitory effect on DNA synthesis. Bryo was further able to antagonize the TPA-mediated effects on proliferation suggesting an (at least partially) different mode of action of these PKC activators. Incubation of MEL-HO and COLO-320 cells with either of the two biomodulators resulted in a rapid and strong increase of c-myc mRNA. The present study emphasizes Bryo as an interesting, natural substance for the study of PKC-mediated biological effects.
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  • 8
    ISSN: 1573-0646
    Keywords: Interferon alpha ; difluoromethylornithine ; doxorubicin ; polyamine metabolism ; advanced malignancies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Interferon (IFN) and conventional cytotoxic chemotherapeutic agents have been successfully combined in various studies. Alpha difluoromethylornithine (DFMO) is a novel antitumor agent which is an inhibitor of polyamine metabolism. A phase I study of IFN 24 × 106 U/m2/day IM (days 3–7), DFMO 9 gm/m2 p.o. daily (days 1–7), and a variable dose of doxorubicin starting at 20 mg/m2 (day 6), of each 28 day cycle was performed. The aim of the study was to determine the maximally tolerable dose of doxorubicin in this combination. Three patients were treated with doxorubicin at 20 mg/m2 and six patients at 40 mg/m2. The dose limiting toxicities were neutropenia, fatigue and fever. All other toxicities were mild and there was no grade IV toxicity. A doxorubicin dose of 40 mg/m2 produced tolerable toxicity and is recommended for phase II studies. No major antitumor effects were seen.
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  • 9
    ISSN: 1573-0646
    Keywords: cyclophosphamide ; interleukin-2 ; kidney neoplasms ; phase II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Thirteen patients with metastatic renal cancer were treated in a phase II trial with interleukin-2, 21.6 million IU/m2 intravenously daily for five days on two consecutive weeks, starting 3 days after the administration of low dose cyclophosphamide 350 mg/m2 intravenously. Treatment cycles were repeated every 21 days. No responses were seen (95% Confidence Interval: 0–22%). The most common toxicities were fever, fatigue, hypotension, nausea/emesis, and myalgia/arthralgia. There were 11 episodes of Grade III toxicity including Grade III hypotension in 7 patients. Because of the significant toxicity and the lack of observed response, the study was discontinued. Cyclophosphamide and interleukin-2 at the dose and schedule used in this study has considerable toxicity and is unlikely to improve on response rates previously seen with other IL-2-based regimens in metastatic renal cancer.
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  • 10
    ISSN: 1573-0646
    Keywords: pancreas ; adenocarcinoma ; gemcitabine ; 2,2′-difluorodeoxycytidme ; phase II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical acitivity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2–20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 × 103/μl (range 1.6–9.3) and the median absolute neutrophil (ANC) nadir was 2.0 × 103/μl (range 0.4–7.2). Thrombocytopenia - 100.0 × 103/μl was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0–245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemcitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.
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