Showing papers on "Doxorubicin published in 1984"

Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II

Abstract: Adriamycin (doxorubicin), a potent antitumor drug in clinical use, interacts with nucleic acids and cell membranes, but the molecular basis for its antitumor activity is unknown. Similar to a number of intercalative antitumor drugs and nonintercalative epipodophyllotoxins (VP-16 and VM-26), adriamycin has been shown to induce single- and double-strand breaks in DNA. These strand breaks are unusual because a covalently bound protein appears to be associated with each broken phosphodiester bond. In studies in vitro, mammalian DNA topoisomerase II mediates DNA damage by adriamycin and other related antitumor drugs.

Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor.

Abstract: EST 5275 is a phase II and III study of fluorouracil plus streptozocin (5-FU plus STZ) or doxorubicin in patients with measurable progressive carcinoid tumor. Among one hundred seventy-two cases with no prior chemotherapy and no heart disease, the response rate was 22% for 5-FU plus STZ and 21% for doxorubicin, while the median response duration and median survival were 31 weeks and 64 weeks for the combination and 26 weeks and 48 weeks for doxorubicin. Thirty-three patients who failed 5-FU plus STZ crossed over to doxorubicin and achieved an 18% response. Of the thirty-five patients who failed on doxorubicin, 29% responded to 5-FU plus STZ. Hematologic toxicity was similar for both treatments; however, the 5-FU plus STZ patients experienced more vomiting but acceptable renal toxicity. Both chemotherapy regimens have antitumor activity in carcinoid tumors.

Intensely potent morpholinyl anthracyclines.

Abstract: 3'-Deamino-3'-(3-cyano-4-morpholinyl)doxorubicin is a new analogue that is 100 to 1000 times more potent than doxorubicin against tumors in cell culture or in mice, that is active by intraperitoneal, intravenous, or oral dosing, and that does not produce chronic myocardial lesions in mice. This analogue was encountered in studies on the reductive alkylation of doxorubicin and daunorubicin with 2,2' - oxybis [acetaldehyde], which constructs a morpholino ring incorporating the amino N. The morpholinyl nitrile byproducts are separated by virtue of their nonbasicity from the expected morpholino derivatives. The 13-dihydro and 5-imino derivatives are also described in this important new class of anthracyclines.

Selective effects of Lipiodolized antitumor agents.

Abstract: Lipiodol Ultra-Fluid (Lipiodol) remains selectively in the tumor for an extended time when applied through arteries feeding the tumor. Although lipophilic antitumor drugs are selective when combined with Lipiodol, wide application of common hydrophilic agents is limited, as these compounds are insoluble in oil. We propose "Lipiodolization" of water-soluble agents using as an intermediate Urografin, a water-soluble contrast medium. Thirteen patients with primary hepatocellular carcinoma were treated with this Lipiodol-Urografin system containing antitumor agents. Marked decrease in serum alpha-fetoprotein (AFP) levels, decrease in tumor size in the hepatic imaging, and histologic studies of the resected specimen revealed this mode of therapy to be effective in 10 of 13 patients (77%) with hepatocellular carcinoma. Lipiodolization of antitumor agents is a new approach to selective cancer chemotherapy.

Combination intraperitoneal chemotherapy with cisplatin, cytarabine, and doxorubicin for refractory ovarian carcinoma and other malignancies principally confined to the peritoneal cavity.

Abstract: Thirty-one patients with refractory ovarian cancer and other malignancies principally confined to the abdominal cavity were treated with an intraperitoneal combination-chemotherapy regimen consisting of cisplatin (100 to 200 mg/m2), cytosine arabinoside (10(-4) to 10(-3) mol/L) and doxorubicin (2 to 18 mumol/L). Sodium thiosulfate was simultaneously administered intravenously to prevent cisplatin-induced nephrotoxicity. Eight of 26 evaluable patients demonstrated clinical response including seven of 17 (41%) with ovarian cancer refractory to frontline chemotherapy. Systemic toxicity was mild except for nausea and vomiting. Abdominal pain secondary to doxorubicin was the major complication of therapy. We conclude that combination intraperitoneal therapy with cisplatin, cytosine arabinoside, and doxorubicin can be safely administered with objective tumor responses observed in patients with ovarian cancer heavily pretreated and in individuals with other malignancies involving the peritoneal cavity. Doxorubic...

Restoration of doxorubicin responsiveness in doxorubicin-resistant P388 murine leukaemia cells.

Abstract: The effects of certain compounds on the in vitro growth rate and the sensitivity to doxorubicin of P388 murine leukaemia cell line and of a doxorubicin-resistant subline (P388/ADR) were studied. The calcium channel blocking activity of these compounds was evaluated by measuring their effects on the sodium-dependent and membrane potential-dependent calcium uptake in synaptic plasma membrane vesicles. At non-inhibitory concentrations, verapamil, dipyridamole, meclizine and nicardipine were highly active in restoring the sensitivity to doxorubicin of P388/ADR cells. Moderately active were propranolol, N-(beta-diethylaminoethyl)-N-(beta-hydroxy-beta-phenylethyl)-2,5-dich loranaline (MDL-6792), thioridazine and chlorocyclizine, while nifedipine, guanethidine, phentolamine, chloroquine and papaverine had zero or only minimal synergistic activity to doxorubicin in this cell line. Doxorubicin synergistic activity could not be demonstrated in the parent drug-sensitive cell line. No sodium-dependent or membrane potential-dependent calcium uptake could be demonstrated in vesicles prepared from plasma membranes of either cell line. There is no correlation between the ability of these compounds to inhibit calcium uptake in synaptic vesicles and their potency in restoring the sensitivity of P388/ADR cells to doxorubicin.

Chemotherapy for multiple myeloma.

Abstract: The effects of eight different drug combinations were evaluated in 256 patients with multiple myeloma. The response rate and time to remission were superior from regimens that added both vincristine and Adriamycin (doxorubicin) to an alkylating agent-prednisone combination. There was no improvement in response rate or survival time from two alternating drug combinations evaluated in an attempt to achieve more marked tumor reductions and to delay the emergence of resistant subclones. The addition of levamisole during remission maintenance did not improve survival time. Results supported the utility of unmaintained remission follow-up in selected patients with marked reductions in myeloma cell mass.

Chemotherapy of diffuse malignant mesothelioma. Phase II trials of single-agent 5-fluorouracil and adriamycin

Abstract: Twenty consecutive patients with a confirmed diagnosis of diffuse malignant mesothelioma of the pleura or peritoneum, previously untreated with chemotherapy, were studied in a Phase II trial of single-agent 5-fluorouracil. One partial response of 24 months was seen. Eleven patients were treated with single-agent Adriamycin (doxorubicin) after progression on 5-fluorouracil, and one partial response of 34 months was seen. It is concluded that 5-fluorouracil has only minimal activity in diffuse malignant mesothelioma. Preliminary data suggest that Adriamycin has little activity as a second-line agent.

Hepatic injury during doxorubicin therapy.

Abstract: Six patients with acute lymphoblastic leukemia manifested liver dysfunction related to doxorubicin hydrochloride therapy. Other causes, eg, infection, hepatitis, posttransfusion reaction, and leukemic infiltration were ruled out. There was close correlation between the administration of doxorubicin and the appearance of hepatic dysfunction. Doxorubicin may produce an idiosyncratic reaction and must be considered a drug with potential liver toxicity.

Recent studies on doxorubicin and its analogues.

Abstract: Publisher Summary Doxorubicin is one member of the anthracycline group of antibiotics and is produced by a variant of the organism that produces daunorubicin (2) (trivial name, daunomycin), the latter drug being preferred in the treatment of acute leukemia, as it is equiactive and lower in cost. Despite its good antitumor activity, doxorubicin is far from an ideal drug as it has both pharmaceutical and toxicological limitations. This chapter focuses on synthetic routes to doxorubicin and other anthracyclines. It discusses the biochemical effects of doxorubicin and analogues of doxorubicin. Most of the work on synthetic routes to anthracyclines has concentrated on doxorubicin (1) and the related compounds, daunorubicin (2) and carminomycin (12). The stimulus has been the low yield of doxorubicin (1) from the fermentation process and the challenge of synthesis of a compound of such complexity. Only recently has attention really widened to synthesis of other natural anthracyclines. The major problem in design of a route is to obtain regiochemical and stereochemical control. New potentially clinically useful analogues have arrived by screening of natural products or by chemically based intuitive semisynthesis and synthesis, rather than by truly rational design.

Menogaril: a new anthracycline agent entering clinical trials

Abstract: Menogaril [menogarol, 7(R)-O-methymogarol, 7-OMEN] is a new anthracycline agent which was chosen for clinical trials based on: a) broad spectrum activity against a panel of murine tumors b) lower cardiotoxicity than doxorubicin in the chronic rabbit model c) differences in biochemical effects from other anthracyclines suggesting a possible difference in mechanism of action d) murine antitumor activity by oral as well as parenteral routes.

Inhibition of plasma membrane NADH dehydrogenase by adriamycin and related anthracycline antibiotics.

Abstract: Doxorubicin (adriamycin) is cytotoxic to cells, but the biochemical basis for this effect is unknown, although intercalation with DNA has been proposed. This study suggests that the cytotoxicity of this drug may be due to inhibition of the plasma membrane redox system, which is involved in the control of cellular growth. Concentrations between 10−6–10−7 M adriamycin inhibit plasma membrane redox reactions >50%. AD32, a form of adriamycin which does not intercalate with DNA, but is cytotoxic, also inhibits the plasma membrane redox system. Thus, the cytotoxic effects of adriamycin, which limit its use as a drug, may be based on the inhibition of a transplasma membrane dehydrogenase involved in a plasma membrane redox system.

Prediction of the response to chemotherapy in acute leukemia by a short‐term testin vitro

Abstract: To detect sensitivity or resistance of leukemic cells to chemotherapy prior to treatment, a short-term incubation method was employed. Blast cells from the peripheral blood or bone marrow of adult patients presenting with different forms of acute leukemia were analyzed for in vitro responsiveness to anticancer drugs in terms of suppression of 3H-uridine incorporation into cellular nucleic acids. The following agents were tested over a wide range of concentrations: Adriamycin, cytosine arabinoside, thioguanine, 6-mercaptopurine, prednisone, and 4-hydroperoxycyclophosphamide. Retrospectively, the in vitro data were compared to the clinical response of the patients to polychemotherapy. In the majority of the patients, in vitro cytotoxic effectiveness of Adriamycin (doxorubicin) and cytosine arabinoside reflected the in vivo situation. The levels of in vitro inhibition that could distinguish between drug-sensitive and drug-resistant diseases appeared to be 30% for Adriamycin and 20% for cytosine arabinoside. No correlation was found between the Adriamycin effect in vitro and the proliferative state (rate of 3H-thymidine incorporation) of the leukemic cell population. Serial in vitro sensitivity testing during the course of disease of various patients proved the ability of the test system to detect acquired resistance to chemotherapeutic agents. Therefore, the assay might serve as a reliable tool in the selection of effective chemotherapy in individual patients suffering from acute leukemia.

Antitumor activity of esorubicin in human tumor clonogenic assay with comparisons to doxorubicin.

Abstract: The new anthracycline analog, esorubicin (4'deoxy-doxorubicin, ESO), was tested against fresh biopsies of human solid tumors in vitro in clonogenic assay and the results were contrasted to those obtained with doxorubicin (DOX). ESO appeared to be significantly more potent on a weight basis than DOX in these studies, and exhibited a spectrum of antitumor activity in vitro that was in general qualitatively similar to that observed with DOX. In vitro antitumor activity was observed in a wide variety of human cancers including anthracycline-sensitive tumor types. ESO has previously been reported to have decreased cardiac toxicity in preclinical models as compared to DOX. Comparative testing of these anthracyclines on granulocyte-macrophage colony-forming units (GM-CFUs) and tumor colony forming units (TCFUs) indicated that the in vitro GM-CFU assay is more sensitive to these myelosuppressive drugs than are TCFUs, and underscores the need for in vivo studies to determine normal tissue toxicity and the therapeu...

Histologic classification as an indication of therapeutic response in malignant lymphoma of dogs.

Abstract: In retrospective evaluation of treatment of canine malignant lymphoma, 12 of 13 dogs that had received doxorubicin alone or in combination with dacarbazine attained complete remission. Doxorubicin had been given alone, with combination chemotherapy being used only when complete remission could not be achieved and maintained with doxorubicin. The response to single or combined chemotherapy was correlated with histologic cell type of the malignant lymphoma. Histiocytic cell types did not respond to doxorubicin alone, but lymphoblastic types did respond. Combination chemotherapy was effective against histiocytic types. A mixed-cell type, which was initially responsive to doxorubicin alone, but not responsive after relapse, was observed to be histiocytic on rebiopsy.

Intensely potent morpholinyl anthracyclines

Abstract: 3'-Deamino-3'-(3-cyano-4-morpholinyl)doxorubicin is a new analogue that is 100 to 1000 times more potent than doxorubicin against tumors in cell culture or in mice, that is active by intraperitoneal, intravenous, or oral dosing, and that does not produce chronic myocardial lesions in mice. This analogue was encountered in studies on the reductive alkylation of doxorubicin and daunorubicin with 2,2' - oxybis [acetaldehyde], which constructs a morpholino ring incorporating the amino N. The morpholinyl nitrile byproducts are separated by virtue of their nonbasicity from the expected morpholino derivatives. The 13-dihydro and 5-imino derivatives are also described in this important new class of anthracyclines.

Randomized Phase III Comparison of Three Doxorubicin-Based Chemotherapy Regimens in Advanced Non-Small Cell Lung Cancer: A Southeastern Cancer Study Group Trial

Abstract: From 1978 to 1981, 537 patients with advanced non-small cell lung cancer were randomly assigned to three regimens containing cyclophosphamide and doxorubicin alone or in combination with methotrexate or cisplatin. Eligible patients had measurable disease and had no prior exposure to chemotherapy. Of the patients entered on the study, 505 were evaluable for toxicity and 488 were evaluable for response. The overall response rate (complete and partial responses) was only 9%. Response rates did not vary significantly with respect to treatment regimen, histologic subtypes, extent of disease, or performance status. There was no survival advantage for any regimen. The major toxicities were myelosuppression and nausea-vomiting. These doxorubicin-based chemotherapy regimens produced disappointing results in patients with advanced non-small cell lung cancer. A search for more active antitumor agents in lung cancer is necessary.

Mutagenic and cytotoxic activity of doxorubicin and daunorubicin derivatives on prokaryotic and eukaryotic cells.

Abstract: The mutagenic and cytotoxic activity of two newly synthesized doxorubicin derivatives and of one daunorubicin derivative were studied in V79 Chinese hamster cells and bacteria (Salmonella typhimurium and Escherichia coli). The results showed that all the compounds tested were cytotoxic and mutagenic for both prokaryotic and eukaryotic cells. However, in both systems, the two 4-desmethoxy- and the 4'-desoxy-derivatives were more active than the parent compounds, indicating that modifications in the aglycone or in the sugar moiety can produce appreciable changes in the biological properties of the anthracycline antibiotics. The in vitro activities observed in this study correlated with the in vivo antitumour potency.

[70] Ethidium binding assay for reactive oxygen species generated from reductively activated adriamycin (Doxorubicin)

Abstract: Publisher Summary The antitumor properties of the anthracyclines, including adriamycin, which shows the broadest activity clinically, correlate with their capacity to bind intercalatively to duplex DNA, although other cellular effects appear to be significant. The administration of adriamycin and daunorubicin is accompanied by severe risk of cardiotoxicity. Growing evidence indicates that this side effect may be related to factors, including the accumulation of the drug in cardiac tissue; reductive enzymatic activation at the chromophore, which in the presence of oxygen produces reactive oxygen species; concomitant oxidative damage of membrane lipids; and the diminished levels in the heart of enzymes, which effect protection against cellular oxidative lesions. Assays designed to detect and quantify the production of individual reactive oxygen species from activated anthracyclines may, therefore, be useful in comparing drugs designed to alleviate this serious clinical limitation of cardiotoxicity.

Comparison of combination chemotherapy programs in advanced adenocarcinoma-large cell carcinoma of the lung: a North Central Cancer Treatment Group study.

Abstract: One hundred and six patients with advanced adenocarcinoma and large cell carcinoma of the lung with no prior chemotherapy were entered in a prospectively randomized trial comparing cyclophosphamide, doxorubicin, and cisplatin versus methotrexate, doxorubicin, cyclophosphamide, and lomustine. The two regimens resulted in nearly identical regression probabilities (36% vs 34%), distributions of time to progression, and survival distributions. The major toxic effects from both regimens consisted primarily of myelosuppression and nausea and vomiting, with severe vomiting occurring more frequently in patients treated with cyclophosphamide, doxorubicin, and cisplatin (43% vs 19%).

Cellular pharmacokinetics of doxorubicin in cultured mouse sarcoma cells originating from autochthonous tumors.

Abstract: We have studied the cellular pharmacology of doxorubicin in a line of mouse sarcoma cells isolated from a dimethylbenzanthracene-induced autochthonous tumor. We have studied the cytotoxicity of the dr

3'-Deamino-4'-epi-3'-hydroxy-daunorubicin and -doxorubicin. Synthesis and antitumor activity.

Abstract: 3'-Deamino-4'-epi-3'-hydroxy-daunorubicin (11) and -doxorubicin (14) have been synthesized.In the in vivo murine P-388 lymphocytic leukemia assay, these two compounds were more active than daunorubicin (1) and doxorubicin (2), respectively. Comparative studies in the P-388 assay indicated 3'-deamino-3'-hydroxydoxorubicin (3) to be more active than its 4'-epimer 14.