Showing papers on "Doxorubicin published in 1981"
TL;DR: The results suggest that the concentration of free sulfHydryl groups in the heart may play a role in the development of doxorubicin cardiac toxicity and that augmenting cardiac nonprotein sulfhydryl group content with n-acetylcysteine may provide a means to enhance the chemotherapeutic index ofDoxorUBicin.
Abstract: This study was undertaken to investigate the effect of exogenous sulfhydryl compound administration on the toxicity of doxorubicin in mice. Pretreatment of CDF1 mice with a pharmacologic dose (2,000 mg/kg) of n-acetyl-l-cysteine 1 h before doxorubicin (20 mg/kg, i.p.) decreased lethality from 100% (n = 44) to 37.7% (n = 53), P less than 0.001. Variation in the timing and dose of n-acetylcysteine significantly diminished its protective activity. Pretreatment with n-acetylcysteine also significantly reduced long-term mortality in animals receiving multiple doses of doxorubicin; 10 wk after the third of three doxorubicin doses (5 mg/kg, i.p.) administered at 2-wk intervals, survival in the n-acetylcysteine pretreated group was 51.4% (n = 35) compared with 16.7% (n = 30) for animals receiving saline before doxorubicin, P less than 0.01. In this experiment, n-acetylcysteine pretreatment also diminished doxorubicin-related losses in total body weight and heart wet weight by 55.2% (P less than 0.05), and 60.9% (P less than 0.02), respectively, compared with animals pretreated with saline. N-acetylcysteine pretreatment also ablated electron microscopic evidence of doxorubicin cardiomyopathy without alleviating morphological features of its toxic effects on the liver or small intestinal mucosa. The cardioprotective action of n-acetylcysteine may be partially explained by the 429 +/- 60% increase in cardiac nonprotein sulfhydryl content (P less than 0.01) that was measured one hour after n-acetylcysteine administration; nonprotein sulfhydryl concentration in the liver at the same time was insignificantly different from control levels. Treatment with n-acetylcysteine also increased the nonprotein sulfhydryl content of P388 leukemia cells nearly threefold; however, it did not after the chemotherapeutic activity of doxorubicin against this murine tumor. Whereas n-acetylcysteine blocked doxorubicin cardiac toxicity, it did not affect the uptake or metabolism of doxorubicin in the heart or liver. These results suggest that the concentration of free sulfhydryl groups in the heart may play a role in the development of doxorubicin cardiac toxicity and that augmenting cardiac nonprotein sulfhydryl group content with n-acetylcysteine may provide a means to enhance the chemotherapeutic index of doxorubicin.
240 citations
TL;DR: It is concluded that anionic liposomes can function as efficacious carriers of doxorubicin and possess improved therapeutic action as reflected by their ability to reduce cardiac toxicity, overcome growth inhibition, and increase antileukemic activity.
Abstract: Anionic liposomes containing doxorubicin were evaluated in mice for therapeutic potential in reducing the risks of chronic cardiotoxicity characteristic of long-term high-dose anthracycline therapy. Doxorubicin first was complexed to phosphatidylcholine and then entrapped in anionic vesicles. Quantitation of myocardial injury was accomplished through examination of thin sections of cardiac tissue by light microscopy. At treatment levels of either 20 or 40 mg/kg (total dose), mice receiving liposomal doxorubicin had toxicity scores indistinguishable from or only slightly greater than those of saline-treated controls. Similar total doses of free drug produced moderate to severe myocardial damage and yielded much higher toxicity scores. Mixture of free doxorubicin with empty liposomes did not alleviate cardiac toxicity, indicating that the drug must be entrapped within phospholipid vesicles for reduction in toxicity. The inhibition of body growth produced by free doxorubicin at both dose levels was also completely eliminated by encapsulation in liposomes. Doxorubicin liposomes were also tested for chemotherapeutic potential against L-1210 and P-388 murine leukemias. In all cases, treatment with liposomal doxorubicin produced increases in life-span greater than that observed for free drug. We conclude that anionic liposomes can function as efficacious carriers of doxorubicin. These vesicles possess improved therapeutic action as reflected by their ability to reduce cardiac toxicity, overcome growth inhibition, and increase antileukemic activity.
173 citations
TL;DR: Left ventricular dysfunction, evident in over half of asymptomatic patients even long after "acceptable" cumulative doses of doxorubicin, may persist for years.
Abstract: Radionuclide cineangiography was used to evaluate 32 patients who sustained long-term remission of soft tissue sarcoma after adjuvant therapy with a cumulative doxorubicin dose from 480 to...
166 citations
TL;DR: It is believed that dihydroxyanthracenedione has significant activity against refractory metastatic metastatic breast cancer and further evaluation is warranted.
Abstract: Thirty-one patients who had metastatic breast cancer extensively pretreated with combination chemotherapy, including doxorubicin, were treated with dihydroxyanthracenedione, 3 to 4 mg/m2bo...
85 citations
Journal Article•
TL;DR: MTX can be effectively administered to patients with CNS tumors by several different approaches, and one patient who became sensitized to CPDG subsequently responded to MTX by intraventricular CXT administration.
Abstract: Forty-three patients with advanced stage III and IV epithelial cancers of the ovary were entered in a prospective randomized study comparing doxorubicin and cyclophosphamide to hexamethylmelamine and cyclophosphamide chemotherapy. No statistical difference in the overall response rates or survival times was demonstrated. However, the combination of doxorubicin and cyclophosphamide was more effective in inducing a response in histologically poorly differentiated cancers than in well-differentiated and moderately differentiated cancers, and the therapeutic implications of this observation are discussed.
69 citations
TL;DR: It is concluded that use of this clinically predicitive in vitro soft agar assay provides a rapid and relatively inexpensive means of simultaneously testing a large number of analogs of a parent compound against a spectrum of human tumors.
Abstract: Ten anthracyclines, including doxorubicin (DX) and daunorubicin (DNR), and eight analogs with modifications in structure or stereochemistry of the aglycone and/or the aminosugar moiety were simultaneously tested in serial vitro titration studies against human adenocarcinomas in the human tumor stem cell assay. More than a two-log range in cytotoxicity of the various anthracyclines was observed with the tumors tested. Marked individual differences in sensitivity of specific tumors (breast, lung, peritoneal) were observed for the various analogs. By assessing average effects on survival of tumor colony-forming units (TCFU) in the tumors tested, the three compounds lacking the methoxyl group in position 4 of the aglycone (4-demethoxyDX, 4-demethoxy-4'-epiDX, 4-demethoxyDNR) all proved to be more cytotoxic than their parent compounds. Compounds modified in position 4' of the aminosugar were on average either as toxic (4' epiDX) or more toxic (4'-deoxyDX and 4'-0-methylDX) to TCFU than the parent compound DX. On average, 11-deoxyDX was less toxic than DX or the other eight anthracyclines tested. The results obtained are also in good general agreement with those previously reported for anthracyclines with human tumors in xenografts or cancer patients. These antitumor results viewed in concert with toxicology studies in normal mice (including evidence of a lack of cardiac toxicity) suggest that 4'deoxyDX may prove to be a clinically useful anthracycline analog. We also conclude that use of this clinically predictive in vitro soft agar assay provides a rapid and relatively inexpensive means of simultaneously testing a large number of analogs of a parent compound against a spectrum of human tumors.
66 citations
TL;DR: It appears that doxorubicin transport in human erythrocytes takes place by free diffusion of the electrically uncharged (unprotonated) doxorbicin molecule through the lipid domain of the cell membrane.
Abstract: The doxorubicin (Adriamycin) transport was investigated by measuring the net efflux of dororubicin from loaded erythrocytes into doxorubicin-free media at 37 degree C. The doxorubicin concentration in the cell water was kept low (5-10 mumol/l). The doxorubicin transport increased with increasing pH. The approx. pKa of the doxorubicin amino group was 7.6(37 degree C, ionic strength 0.15). Phloretin, l-alcohols and local anaesthetics increased doxorubicin transport after the fashion of the effect of these drugs on membrane transport of lipophilic compounds. Several inhibitors of facilitated transport systems in erythrocytes did not affect doxorubicin transport. The calcium and magnesium concentration in the cell water (0-2 mmol/l) did not affect doxorubicin transport. It appears that doxorubicin transport in human erythrocytes takes place by free diffusion of the electrically uncharged (unprotonated) doxorubicin molecule through the lipid domain of the cell membrane.
56 citations
TL;DR: 5-fluorouracil administered in an adequate weekly dosage is established as an effective single agent in some patients with stage D carcinoma of the bladder or prostate, however, there is no significant added benefit as measured by survival obtained for these patients by combining cyclophosphamide and doxorubicin with 5-fluorbicin.
44 citations
Journal Article•
TL;DR: Experimental results obtained using doxorubicin against prostate, sarcoma, and larynx tumors also parallel the reported clinical data.
Abstract: In order to establish the usefulness of the human tumor-nude mouse system as a predictive screen for anticancer agents, 17 tumors (3 breast, 3 colon, 3 lung, 3 melanoma, 2 ovary, 1 prostate, 1 sarcoma, and 1 larynx), serially transplantable in athymic mice, were used to study antitumor activity of doxorubicin (Adriamycin). BALB/c nude mice were treated i.v. on a weekly basis for 3 to 4 weeks, starting when the tumor volume became relatively large (advanced stage of tumor treatment). All the tumors except lung tumor T 293 showed a 90 to 100% take rate and stable growth. Doxorubicin, at dose levels of 6 and 10 mg/kg/injection i.v. every week for 3 weeks, showed significant activity against all of the three breast tumors studied. As was expected on the basis of clinical data, doxorubicin showed no antitumor activity against the three different colon tumors. In the case of lung tumors, statistically significant activities against oat cell carcinoma T 293 and epidermoid carcinoma T 222 were observed. In contradiction to clinical data, doxorubicin was found to have significant activity against various melanomas studied and slight but not statistically significant activity against ovarian tumor T 17. Experimental results obtained using doxorubicin against prostate, sarcoma, and larynx tumors also parallel the reported clinical data.
43 citations
TL;DR: A case report of complete remission of malignant thymoma in which the combination of cyclophosphamide, doxorubicin and cis‐platinum (CAP) was used is reported.
Abstract: Systemic chemotherapy as a mode of therapy in metastatic malignant thymoma has never been systematically evaluated. Chemotherapeutic agents, including doxorubicin, cyclophosphamide, cis-platinum, nitrogen mustard, prednisone or combination of agents like MOPP have produced tumor remission. A case report of complete remission of malignant thymoma in which the combination of cyclophosphamide, doxorubicin and cis-platinum (CAP) was used is reported.
43 citations
TL;DR: The preparation was active both in vitro and in vivo, indicating the desirability of testing other macromolecules, such as dextran5, as carriers for trypanocidal drugs.
Abstract: The anthracycline antibiotic daunorubicin is, in vitro, one of the most potent trypanocidal agents reported1; it permanently abolishes the infectivity of African trypanosomes at less than nanomolar concentrations. In contrast, other anthracyclines such as doxorubicin and nogalamycin must be present in milli-molar concentrations to achieve the same effect (Table 1). Despite its uniquely high activity in vitro, daunorubicin is totally inactive against trypanosomes in infected rodents1. An investigation of this lack of in vivo activity suggested that uptake into trypanosomes is only transient2. We therefore tried to prolong exposure of trypanosomes to the drug by coupling it to a carrier macromolecule. The use of such a carrier should delay removal of the drug from the blood and simultaneously exploit the endocytotic properties of trypanosomes. Ferritin and albumin were chosen as potential carriers as these proteins are endocytosed by trypanosomes3,4. We report here that when the drug was attached by a stable linkage, activity was not maintained, but when attached by a labile covalent linkage the preparation was active both in vitro and in vivo, indicating the desirability of testing other macromolecules, such as dextran5, as carriers for trypanocidal drugs.
TL;DR: 4′-Deoxydoxorubicin reached the same tissue levels as doxorubsicin in all the organs tested except in spleen and lung, where a higher peak was found in the animals treated with the new analog.
Abstract: The pharmacokinetic of 4′-deoxydoxorubicin, a new analog of doxorubicin, was compared with that of its parent compound in mice treated with equal and equiactive doses. The levels of total fluorescence due to the initial drugs and to metabolites were determined in tissue extracts by fluorometry. 4′-Deoxydoxorubicin reached the same tissue levels as doxorubicin in all the organs tested except in spleen and lung, where a higher peak was found in the animals treated with the new analog. The rate of elimination of 4′-deoxydoxorubicin from the organs tested was higher than that of doxorubicin.
TL;DR: Patients with advanced or recurrent endometrial adenocarcinoma treated with a combination of cyclophosphamide, doxorubicin, 5-flucrouracil, and megestrol acetate had objective responses and there were no instances of cardiotoxicity.
Journal Article•
TL;DR: The cytotoxicity of DM is correlated with a higher fluorescence intensity of blast cells, lymphocytes and granulocytes when treated with DM as compared to AM, and the fluorescence of AML blast cells is significantly lower after treatment with DM than with AM.
Journal Article•
TL;DR: The combination of doxorubicin and cyclophosphamide has demonstrable, albeit limited, activity against metastatic endometrial cancer.
Journal Article•
TL;DR: It is demonstrated that therapeutic efficacy of immunotherapy depends critically on the choice of an appropriate agent and route of administration and, to a lesser extent, on the dose and schedule used.
Abstract: A comprehensive study of nonspecific immunotherapy has been conducted in an established murine model of ovarian cancer in order to determine the relative effectiveness of commonly used bacterial immunostimulants, the importance of the route and schedule of administration of these agents, and their effects in combination with chemotherapy. Implants of 105 or 106 ovarian tumor cells i.p. kill all syngeneic C3HeB/FeJ mice within 25 days. Corynebacterium parvum (700 µg/mouse i.p. 24 hr after a 105 tumor cell inoculum) cures 75% of the mice; in contrast, neither i.v. nor s.c. administration improves survival rates. After the same tumor challenge, Bacillus Calmette-Guerin was minimally effective at extremely high doses only, while the methanol extraction residue of B. Calmette-Guerin was ineffective. Two days after an implant of 106 tumor cells, neither cyclophosphamide, nor cis -diamminedichloroplatinum(II) (cisplatin), nor C. parvum increased survival. Combination of C. parvum with cyclophosphamide or cisplatin resulted in a synergism shown by the 40 and 60% cure rates, respectively. However, combination of C. parvum with an active agent, doxorubicin, resulted in toxicity even in untumored animals.
This study demonstrates that therapeutic efficacy of immunotherapy depends critically on the choice of an appropriate agent and route of administration and, to a lesser extent, on the dose and schedule used. The observation provides a rationale for carefully conducted Phase I and Phase II studies of treatment with bacterial immunostimulants, alone or in combination with chemotherapy, in human ovarian cancer.
Journal Article•
TL;DR: The Madison 109 lung carcinoma was responsive to many different classes of clinically active agents and can serve as a useful tool in the screening of drugs with such potential, and may be particularly useful in screening analogs of camptothecins, nitrosoureas, bleomyCins, and mitomycins.
Abstract: The Madison 109 lung carcinoma (M109) was evaluated as a model for the screening of antitumor agents. Thirty-five drugs with established antitumor activity were assayed in mice implanted ip or sc with M109. Depending on the mode of tumor implantation, drugs representing those affecting nucleic acids (through binding, interacalating, or inducing single-strand breaks), various alkylating agents, mitotic inhibitors, antimetabolites, and immunomodulators were able either to inhibit the growth of sc M109 or to extend the lifespan of mice given M109 ip. The ip implanted tumor was, for example, markedly affected (median survival time of treated/control mice, x 100: greater than or equal to 200% with occasional cures) by doxorubicin, mitomycin C, 10-hydroxy camptothecin, and dihydroxyanthraquinone. The sc implanted tumor, however, was markedly affected (treated - control of greater than or equal to 12 days with regard to median time to grow 1-g tumors) by bleomycin and an analog, talisomycin, and by 6-thioguanine. The M109 was responsive to many different classes of clinically active agents and can serve as a useful tool in the screening of drugs with such potential. It may be particularly useful in screening analogs of camptothecins, nitrosoureas, bleomycins, and mitomycins as well as for evaluating anthraquinones, anthracyclines, mitotic inhibitors, antimetabolites, and immunomodulators.
Journal Article•
TL;DR: In mice bearing transplanted MLV-M leukemia, the effects of the combination of ICRF-159 with DR or DX were not superior to those ofDR or DX treatment on either tumor growth or lifespan, and a higher antimetastatic activity was observed in the groups treated with a combination of toxic doses of DR and I CRF-150 than in the group treated with tolerated doses of the antibiotic.
Abstract: We have investigated the effect of ICRF-159 on the toxicity of daunorubicin (DR) and doxorubicin (DX) given iv, and the effectiveness of ICRF-159 combined with DR or DX on the growth of transplantable MLV-M (murine leukemia virus-Moloney) leukemia, MS-2 solid sarcoma, and pulmonary MS-2 metastases in mice. The injection of ICRF-159 concurrently with the administration of DR resulted in a marked decrease in the toxicity of the antibiotic. However, when DX was injected concurrently with ICRF-159 an increase in antibiotic toxicity was observed, except when ICRF-159 was employed at a very low dosage. ICRF-159 administered alone did not influence the tumor growth in the systems tested and did not result in antimetastatic activity. In mice bearing transplanted MLV-M leukemia, the effects of the combination of ICRF-159 with DR or DX were not superior to those of DR or DX treatment on either tumor growth or lifespan. The treatment of MS-2 tumor with the ICRF-159 and DX combination neither produced a therapeutic synergism (therapeutic response superior to the maximum response obtainable by either agent independently) nor antagonized the antineoplastic action of DX. A marked inhibition of tumor growth and increase in lifespan were observed in the mice treated with a high dose of DR (10 mg/kg/injection) plus ICRF-159 (50 mg/kg/injection). We have also examined, on MS-2 lung metastases, the effectiveness of surgical-adjuvant combination chemotherapy with DR or DX plus ICRF-159 injected at different times with respect to surgery. A synergistic effect of DX or DR with ICRF-159 was observed when the drug treatment was performed before the surgery, or both before and after the surgery. No synergistic effect of DX or DR with ICRF-159 on MS-2 lung metastases was found when the MS-2 lung metastases were treated after the surgery. A higher antimetastatic activity was observed in the groups treated with a combination of toxic doses of DR and ICRF-150 than in the groups treated with a combination of toxic doses of DR and ICRF-159 than in the groups treated with tolerated doses of the antibiotic.
TL;DR: Isopycnic and differential centrifugations indicate that DNR could be associated with nuclear DNA and to a smaller extent with lysosomes and after injection of free or complexed DOX the drug is almost exclusively associated with the nuclear DNA.
Patent•
23 Mar 1981TL;DR: In this article, 3'-deamino-3'-(4-methoxy-1-piperidinyl) derivatives of daunorubicin and DOXORUBICIN have been described.
Abstract: Described are 3'-deamino-3'-(4-methoxy-1-piperidinyl) derivatives of daunorubicin and doxorubicin having the formula ##STR1## wherein R is COCH3 or --CHOHCH3 in the case of daunorubicin derivatives, or is COCH2 OH or --CHOH--CH2 OH in the case of doxorubicin derivatives together with their pharmaceutically acceptable acid salts The compounds have utility as antitumor agents
01 Jan 1981
Journal Article•
TL;DR: Twenty women with recurrent ovarian adenocarcinoma received a monthly four-drug combination of cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin as second-line chemotherapy; there were no objective responses to this regimen.
Abstract: Twenty women with recurrent ovarian adenocarcinoma received a monthly four-drug combination of cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin as second-line chemotherapy. There were no objective responses to this regimen. This is in contrast to the 49% response rate reported by Kane et al using these four drugs and the 63% response rate reported by Vogl et al using three of these drugs as second-line chemotherapy. The differences in the three regimens are reviewed; however, we could not identify reasons sufficient to account for the disparity in response rates.
TL;DR: Peripheral blood leukemic cells from 11 patients with acute myelocytic leukemia were assayed for DNA damage produced by exposure to adriamycin for 4 h, and the results were compared to therapeutic responses of the patients to combination therapy with adRIamycin and ara-C.
01 Jan 1981
TL;DR: The most successful programs for treatment of acute non-lymphoblastic leukemia (ANLL) in adults now cause remission in about 70–80% of previously untreated patients, but most patients relapse despite maintenance therapy given at certain intervals.
Abstract: The anthracycline antibiotics daunorubicin (DNR) and doxorubicin (DOX, adriamycin) play a prominent role in the treatment of acute leukemia.1,2 The most successful programs for treatment of acute non-lymphoblastic leukemia (ANLL) in adults now cause remission in about 70–80% of previously untreated patients. But most patients relapse despite maintenance therapy given at certain intervals. The response rate is then much lower and most of these patients are resistant to the drugs which initially caused remission.
TL;DR: Since the protein-bound drug is only partially dissociated by physical procedures including gel-electrophoresis, column-chromatography and solvent extraction, the formation of a covalent bond is suggested.
Abstract: The results of a comparative investigation on the interaction of doxorubicin (adriamycin) and daunorubicin with serum proteins are reported Whereas a strong interaction occurs in vitro between doxorubicin and human serum proteins, no appreciable binding to proteins could be detected for daunorubicin under similar experimental conditions Since the protein-bound drug is only partially dissociated by physical procedures including gel-electrophoresis, column-chromatography and solvent extraction, the formation of a covalent bond is suggested The doxorubicin binding to serum proteins is apparently nonselective for a class of proteins; it is strongly reduced in acid conditions and slightly dependent on the ionic strength Two tentative reaction mechanisms have been considered
TL;DR: In vitro studies on the uptake of 4′-O-methyldoxorubicin in the Ehrlich ascites tumor cells indicated that the observed cross-resistance was partly due to a decreased drug uptake in the resistant cells because of an increased extrusion of the drug, in accordance with previous findings on the mechanism of acquired resistance to doxorubsicin.
Abstract: A new analog of doxorubicin, 4′-O-methyldoxorubicin, was previously reported to have a pronounced activity agianst L1210 leukemia, which shows a natural partial resistance to doxorubicin itself. In the present study, lines of P388 leukemia and Ehrlich ascites tumor with acquired resistance to doxorubicin were found to be cross-resistant to 4′-O-methyldoxorubicin, indicating that the natural and the acquired resistance to doxorubicin involve different mechanisms. In vitro studies on the uptake of 4′-O-methyldoxorubicin in the Ehrlich ascites tumor cells indicated that the observed cross-resistance was partly due to a decreased drug uptake in the resistant cells because of an increased extrusion of the drug, in accordance with previous findings on the mechanism of acquired resistance to doxorubicin.
TL;DR: Cytofluorimetry showed a broad spread of intracellular daunorubicin fluorescence which increases with cell size, and increasing external concentration caused a more rapid incorporation as well as a quicker release from the cells.
TL;DR: It is concluded that dosage reduction may reduce toxicity with no concomitant decrease of antileukemic activity of doxorubicin.
Abstract: The dose response curves of doxorubicin for hematopoietic rat bone marrow cells were investigated and compared with the dose-response curves of doxorubicin for leukemia cells from bone marrow and spleen of rats inoculated with an acute myelocytic leukemia (BNML). Various assays were used to determine the cytotoxicity of doxorubicin. It was found that the inhibition of DNA synthesis by doxorubicin compared well with results obtained with in vivo assays for the determination of clonogenic hematopoietic (CFU-S) and leukemic (LCFU-S) cells. It was found that doxorubicin at concentrations ranging from 0.1–1.0 μg · 10-7 cells inhibits DNA synthesis of leukemic cells to 60% and that of hematopoietic cells to 90%. Higher doxorubicin concentrations further inhibit DNA synthesis of only hematopoietic cells. These results were confirmed with clonogenic assays. Pre-treatment with the S phase-specific drug arabinoside cytosine (ara-C) increased the efficacy of doxorubicin in vitro significantly. In view of the doxorubicin concentrations in bone marrow obtained in vivo (≥1 μg · 10-7 cells), it is concluded that dosage reduction may reduce toxicity with no concomitant decrease of antileukemic activity of doxorubicin.
TL;DR: Doxorubicin and daunorubsicin can cause dose-dependent cardiomyopathy in children and adults and risk factors that predispose patients to cardiomeopathy include advanced a...
Abstract: Excerpt To the editor: Doxorubicin and daunorubicin can cause dose-dependent cardiomyopathy in children and adults (1, 2). Risk factors that predispose patients to cardiomyopathy include advanced a...