Showing papers on "Doxorubicin published in 1979"

Risk factors for doxorubicin-induced congestive heart failure.

Abstract: Potential risk factors responsible for development of doxorubicin-induced congestive heart failure were examined through retrospective analysis of 4018 patient records. The overall incidence of drug-induced congestive heart failure was 2.2% (88 cases). The probability of incurring doxorubicin-induced congestive heart failure was related to the total dose of doxorubicin administered. There was a continuum of increasing risk as the cumulative amount of administered drug increased. A weekly dose schedule of doxorubicin was associated with a significantly lower incidence of congestive heart failure than was the usually employed every 3-week schedule. An increase in drug-related congestive heart failure was also seen with advancing patient age. Performance status, sex, race, and tumor type were not risk factors. These data will enable clinicians to better estimate the risk/benefit ratio in individual patients receiving prolonged administration of doxorubicin. They also provide a basis for the investigation of less cardiotoxic anthracycline analogues or for designing measures to prevent doxorubicin-induced cardiomyopathy.

Adriamycin and the Heart

Abstract: Doxorubicin, or adriamycin, is one of the most effective chemotherapeutic agents for cancer. It has an established role in the treatment of the acute leukemias and the lymphomas. In contrast to most other drugs, it has substantial activity in solid tumors as well. It is the single most effective agent in the treatment of breast cancer and soft-tissue sarcomas, and it has substantial activity in the childhood tumors, testicular cancer, gastric cancer, ovarian cancer and oat-cell carcinoma of the lung.1 The acute dose-limiting toxicity of this drug, as with most chemotherapeutic agents, is myelosuppression. Other side effects, including nausea, vomiting . . .

The effect of doxorubicin on hepatic and cardiac glutathione.

Abstract: The effect of the antitumor antibiotic doxorubicin on glutathione and glutathione disulfide levels in mouse heart and liver has been evaluated. The glutathione content of hepatic and cardiac tissue from saline-treated controls exhibited a statistically significant diurnal variation. Doxorubicin administration produced a dose-related decrease in hepatic glutathione which was not blocked by pretreatment with the free radical scavenger alpha-tocopherol; a lesser drop in cardiac glutathione was also documented. These changes may play an important role in the metabolism and toxicity of doxorubicin.

Improved combination chemotherapy in advanced gastric cancer.

Abstract: Thirty-five patients with advanced-stage metastatic or unresectable gastric adenocarcinoma were given combination chemotherapy consisting of fluorouracil, doxorubicin, and 1,3-bis (2-chlorbethyl)-1-nitrosourea. Two patients achieved complete remission and 16 partial remission to give an overall response rate of 52%. Six further patients (17%) had stable disease, while in 11 (31%) the disease showed clear-cut progression despite treatment. The only pretreatment factors that suggested poor prognosis were poor initial patient performance and the stomach as the predominant site of disease. Patients responding to treatment had a significantly longer time to relapse (median 48 weeks) than patients with stable disease (median 16 weeks) and a significantly improved survival time (medians, 52 weeks with 30% of patients9 living at 88 weeks and 32 weeks with all dead at 64 weeks respectively). Comparing these results with those in other reports indicated that the three-drug combination chemotherapy consisting of fluorouracil, doxorubicin, and either a nitrosourea or mitomycin was superior to single and two-drug regimens and currently represents the optimum treatment for advanced-stage gastric cancer. Gastric adenocarcinoma should now be considered to be a gastrointestinal malignancy that is relatively susceptible to chemotherapy, and studies of these improved chemotherapeutic regimens as post-surgical adjuvants may lead to further improvements in prognosis.

Postoperative Adjuvant Chemotherapy With Fluorouracil, Doxorubicin, Cyclophosphamide, and BCG Vaccine: A Follow-up Report

Abstract: Two hundred twenty-two patients with stage II or III breast cancer following regional therapy were treated with a combination of fluorouracil, doxorubicin hydrochloride (Adriamycin), cyclophosphamide, and BCG vaccine. At 54 months of study (median follow-up, 30 months), the estimated proportions remaining disease-free two and three years after surgery were 83% and 78%, respectively, in the chemotherapy group and 64% and 55%, respectively, in 151 historical control patients. Estimated two- and three-year survival rates were 93% and 89%, respectively, in the chemotherapy group and 84% and 58%, respectively, in the control patients. Congestive heart failure has developed in three patients, possibly related to the use of doxorubicin. Adjuvant chemotherapy with these drugs was effective in prolonging the disease-free interval and survival of patients irrespective of menopausal status, degree of nodal involvement, or stage of the disease. (JAMA242:1509-1513, 1979)

Mechanism of action of the anthracycline anti-tumor antibiotics, doxorubicin, daunomycin and rubidazone: preferential inhibition of DNA polymerase alpha.

Abstract: The effects of the anthracycline anti-tumor antibiotics, doxorubicin, daunomycin and rubidazone upon 3H-TTP incorporating activities of partially purified DNA polymerases and isolated liver nuclei were studied. Doxorubicin, daunomycin and rubidazone inhibited DNA polymerases α and β in proportion to drug dose, with consistent preferential inhibition of the α polymerase in comparison to the β polymerase for all three drugs. Studies with isolated nuclei, including normal liver nuclei (predominantly β polymerase activity), regenerating liver nuclei (α>β activity) and Brij 58, MgCl2-extracted regeneratingliver nuclei (predominantly α activity), showed inhibition in the order Brij 58, MgCl2-extracted regenerating regenerating normal nuclei, corroborating the results obtained with the separate polymerase activities. The elevations in DNA melting temperatures caused by the binding of doxorubicin, daunomycin and rubidazone correlated with the degrees of inhibition of the polymerase activities, suggesting that intercalative binding is the mechanism by which these three agents inhibit the DNA polymerases. It is suggested that preferential inhibition of the α polymerase (the putative replicative polymerase) in comparison to the β polymerase (the presumed repair polymerase) may underlie the Cell Cycle Specific character of the mechanism of action of these anthracycline antibiotics.

DNA-binding parameters of daunorubicin and doxorubicin in the conditions used for studying the interaction of anthracycline-DNA complexes with cells in vitro.

Abstract: Affinity constants of daunorubicin and doxorubicin for DNA at 37 degrees C and in presence of 10% serum were determined by an optical method and calculated from Scatchard plots. Values from 0.10 to 0.12 and from 0.13 to 0.16 X 10(6) M-1 were obtained for daunorubicin and doxorubicin, respectively. According to these affinity constants, the amounts of free drugs were calculated for various concentrations of daunorubicin-DNA or doxorubicin-DNA and for various molar ratios. In a large range of concentrations there is rather stable concentration of both free drugs, and these concentrations are inversely proportional to the nucleotides/drug ratio. The amount of free drug present in the medium is low as long as the concentration of daunorubicin-DNA or doxorubicin-DNA is higher than 1 microgram/ml (expressed as drug concentration). At lower concentrations, however, the percentage of free drug increases very sharply.

Determination of daunorubicin, doxorubicin and their fluorescent metabolites by high-pressure liquid chromatography: plasma levels in DBA2 mice.

Abstract: A rapid and nondestructive analytic method has been developed to separate and quantitate daunorubicin, doxorubicin, and their metabolites in biological fluids. This method combines the efficiency of high-pressure liquid chromatography and the sensitivity of fluorescence monitoring. The drug plasma levels achieved after IV administration of either daunorubicin or doxorubicin at 7 mg/kg into DBA2 mice were studied. The plasma disappearance curves are biphasic with a halflife of 1 min for the first elimination phase. In urine extracts, 13-hydroxy derivatives represent 80% of the fluorescence after injection of daunorubicin and only 4% after administration of doxorubicin.

Comparative trial of low-dose adriamycin plus cyclophosphamide with or without additive hormonal therapy in advanced breast cancer.

Abstract: We treated 56 women with advanced metastatic breast cancer who had not received prior chemotherapy in a comparative trial of cytotoxic chemotherapy with low-dose adriamycin plus cyclophosphamide alone or in combination with the androgenic steroid calusterone. The response rate to chemohormonal therapy (65%) could not be shown to be statistically better than that for chemotherapy alone (53%) for this size patient population. However, the median remission duration (21.5 months) was significantly prolonged over the 11.5-month remission duration for chemotherapy alone (p = 0.03). The median survival of the chemohormonal therapy group was 23.5 months, whereas that for chemotherapy alone was 13.5 months (p = 0.05). These results indicate that the addition of a potent hormonal agent to effective cytotoxic chemotherapy improves the results of treatment of women with metastatic breast cancer.

Comparative study in mice of the toxicity, pharmacology, and therapeutic activity of daunorubicin-DNA and doxorubicin-DNA complexes.

Abstract: We have compared the toxicologic, pharmacologic, and therapeutic properties of the DNA complexes of daunorubicin and doxorubicin, after intravenous (IV) administration into mice. The overall toxicity of doxorubicin is significantly reduced after IV injection as a DNA complex while daunorubicin-DNA is as toxic as free daunorubicin. On hemopoietic stem cells, daunorubicin-DNA was found to be more cytotoxic than daunorubicin, while the opposite was observed with doxorubicin and doxorubicin-DNA. Both complexes are more effective than the corresponding free drugs on the L 1210 murine leukemia, when given IV at equitoxic doses. The tissue uptake in mice, after IV administration, is generally lower when the drugs are given bound to DNA. The stability of the two DNA complexes is very different in the bloodstream: daunorubicin-DNA behaves more like a prodrug of daunorubicin, while doxorubicin-DNA, remaining stable in the bloodstream, meets much more the requirements of an ideal drugmacromoleculare carrier entity.

Fluorescence assay of tissue distribution of 4-demethoxydaunorubicin and 4-demethoxydoxorubicin in mice bearing solid tumors.

Abstract: The tissue distribution of 4-demethoxydaunorubicin and 4-demethoxydoxorubicin was studied in comparison with that of their parent compounds, daunorubicin and doxorubicin, in mice bearing transplanted tumors. The doses administered were equal or equitoxic to those of their parent compounds. The levels of total fluorescence due to initial drugs and metabolites were determined on tissue extracts by fluorometry. After administration of equal doses of daunorubicin and 4-demethoxydaunorubicin, the calculated Cxt values of 4-demethoxydaunorubicin equivalents were higher than those for daunorubicin in all the organs tested except the heart. In animals treated with equitoxic doses, lower 4-demethoxydaunorubicin levels were found in all the organs tested. In mice treated with equitoxic doses of doxorubicin and 4-demethoxydoxorubicin, 4-demethoxydoxorubicin reached higher drug concentrations than doxorubicin in spleen and liver, whereas in all the other organs tested lower drug levels were found. The rate of drug disappearance from organs was slower in animals treated with 4-demethoxyderivatives than in those treated with their parent drugs.

Uptake of free and DNA-bound daunorubicin and doxorubicin into human leukemic cells.

Abstract: Leukemic cells from seven patients with acute nonlymphoblastic leukemia and granulocytes, and mononuclear cells from three healthy controls were isolated by centrifugation on metrozoate-dextran. The intracellular accumulation of both the free and DNA-bound forms of daunorubicin and doxorubicin was studied in vitro. The uptake of unbound daunorubicin was higher than that of doxorubicin. At drug concentrations of 1.75 μM and higher the uptake of the free drugs was greater than that of the bound forms, but at lower drug concentrations the uptake was about the same. This could at least partly be explained by a greater dissociation of the DNA-drug complexes at lower drug concentrations. The uptake into normal leukocytes was of the same order of magnitude as that into leukemic cells. There was a great interindividual variation in the accumulation of both free and DNA-bound drugs in the cells from leukemic patients. This variation might be of importance for the prediction of individual sensitivity to the different drugs.

Effects of daunorubicin and doxorubicin, free and associated with DNA, on hemopoietic stem cells.

Abstract: We have compared daunorubicin (DNR)-DNA with free DNR and doxorubicin (DOX)-DNA with free DOX for their effects in vivo in mice on pluripotent stem cells and granulocytic committed stem cells. Dose-survival, time-survival, and recovery curves were obtained after one i.v. injection of either drug. The dose-survival curves of colony-forming units-spleen (CFU-S) and colony-forming units-committed stem cells (CFU-C) were exponential in shape with both agents. DNR-DNA appeared more toxic to the hemopoietic precursor cells than did free DNR. In contrast, DOX-DNA was less toxic toward CFU-S and as toxic as DOX toward CFU-C. Time-survival curves indicated a minimum level of CFU-S and CFU-C at about 33 hr. After that, the recovery of CFU-S was rapid for DNR-treated mice but remained below 50% of the controls on Day 12 for the DNR-DNA-treated group. In mice previously given injections of DOX or DOX-DNA, the recovery of the CFU-S was more protracted in time with a better recovery in mice treated with DOX-DNA. Both DNR and DNR-DNA induced an initial CFU-C decrease followed by a rapid but transient rise with a maximum on Day 4 after chemotherapy. On Day 12, the CFU-C recovery was still incomplete in both DNR- and DNR-DNA-treated mice. In the groups treated with DOX, the CFU-C recovery was more important after DOX-DNA complex than after free DOX. The results are discussed in view of the “lysosomotropic chemotherapy” hypothesis.

Clinical activity of detorubicin: a new anthracycline derivative.

Abstract: The anthracycline derivatives are intercalating drugs which are of major importance in the treatment of leukemias and in the management of solid tumors. Structural analogs have been prepared by semisynthetic modifications in an attempt to extend the spectrum of antitumor activity and to reduce toxicity (acute myelosuppression and cardiotoxicity). This report concerns our preliminary clinical experience in 111 patients who received detorubicin. Two dose schedules were used in acute leukemia patients. Sequential doses were active in acute leukemia relapses but the mucous membrane toxicity was excessive; more recently, intermittent doses proved active in acute leukemia relapses (one 6-mg/kg dose) and in a patient with resistant Burkitt's lymphoma. In non-Hodgkin's lymphomas, a complete response rate of 71% was achieved with an intermittent schedule (3 mg/kg/day X 3 weeks). A remarkable shrinkage of skin involvement was also observed. Detorubicin showed a high activity in mycosis fungoides (five regressions among six patients) and some activity in soft tissue sarcomas, osteosarcomas, and various solid tumors.

Repair kinetics of DNA, RNA and proteins in the tissues of mice treated with doxorubicin.

Abstract: Experiments in mice treated with a single 10 mg/kg dose of doxorubicin (adriamycin) i.p. revealed considerable reduction in the incorporation of 3H-thymidine in DNA and of 3H-uridine in RNA, in the spleen and liver, and at mitochondrial and non-mitochondrial level in the heart. Although protein syntheses in the heart and spleen were not reduced by the drug to any great degree, they took 10 days to return to normal; conversely, liver protein syntheses were not inhibited at all and indeed presented signs of stimulation.

Inhibition of drug oxidation and stimulation of NADPH oxidase in vitro by doxorubicin and triferric-doxorubicin.

Abstract: The electrophilic properties of the quinone-hydroquinone configuration of anthracycline antibiotics suggests a possible influence on cytochrome P-450-mediated mono-oxygenase reactions. Both doxorubicin and triferric-doxorubicin (a derivative in which the quinone groups are blocked with iron) showed a similar dose-dependent inhibition of liver microsomal drug metabolism. A doxorubicin concentration-related stimulation of NADPH oxidase activity was found to be linear but that for triferric-doxorubicin was asymptotic. Neither inhibitor affected the activity of cytochrome c reductase, cytochrome b5 reductase or cytochrome P-450 reductase. However, doxorubicin did potentiate the inhibitory effect of aniline on cytochrome P-450 reductase and on ethylmorphine metabolism. It is concluded that these anthracyclines inhibit drug metabolism in vitro not by their electron-withdrawing potential but in a manner more similar to that described for type II compounds.

Chemotherapy for sarcoma of the stomach.

Abstract: The results of chemotherapy for patients with advanced leiomyosarcoma of gastric origin were analyzed. A total of 23 single-agent and multi-drug regimens were given to 17 patients. DTIC and adriamycin (ADR) were the most commonly used chemotherapeutic agents. ADR was used alone or in combination in 13 patients, resulting in partial responses in two patients and disease stabilization in seven. One of the partial responses was obtained with the ADR-DTIC combination and the other was obtained with the cyclophosphamide-vincristine-ADR-DTIC combination. The survival duration for the responders was significantly longer than that obtained for those patients who had disease stabilization or progression. The results of the study show that leiomyosarcoma of gastric origin is less sensitive to chemotherapeutic agents than leiomyosarcomas of other sites, as reported in the literature. New approaches based on the natural history of the disease and with potential to improve the results of treatment of gastrointestinal sarcomas are indicated.

Combination chemotherapy with a new anthracycline glycoside, aclacinomycin-a, and active drugs for malignant lymphomas in p388 mouse leukemia system.

Abstract: Aclacinomycin-A is a new anthracycline glycoside and has less cardiotoxicity than adriamycin. In an attempt to provide an experimental model of a phase III study of aclacinomycin-A, particularly for the treatment of malignant lymphomas, various therapeutic designs of combinations of this drug with other conventional agents were investigated using a P388 mouse leukemia system. Aclacinomycin-A showed no treatment schedule dependency in this tumor system and the optimal dosage of this drug was twice higher than that of adriamycin on each treatment schedule; i.e., single treatment on day 1, three treatments on days 1, 5, and 9, or 10 treatments on every other day from days 1 to 19 after an inoculation of 10(6) leukemic cells on day 0. This antibiotic was ineffective against an adriamycin-resistant subline of P388 leukemia. Among combinations of aclacinomycin-A with cyclophosphamide, vincristine, procarbazine, or bleomycin, the combinations of aclacinomycin-A with cyclophosphamide or vincristine showed a therapeutic synergism in P388 leukemia system.

Chemotherapy in the management of ovarian carcinoma: a review.

Abstract: Ovarian cancer is the commonest gynaecological cancer causing death. Young (1975) estimates that one hundred thousand American women died from this malignancy in the last decade. It is disappointing that optimal therapy for local as well as disseminated disease is still not known. The difficulties that face the surgeon, radiotherapist and chemotherapist in ovarian carcinoma include the problem of diagnosing the condition early, being sure that the tumour is completely eradicated and detecting early recurrence. This is partly due to the biological behaviour of the tumour, with its propensity to early transcoelomic spread to sites such as the diaphragmatic surface of the liver, where it is difficult to detect. In only one quarter of women is the disease diagnosed while still confined to the ovaries; more than half have abdominal extension of the disease or metastases at diagnosis. The International Federation of Gynaecologists and Obstetricians (FIGO) staging is given in Table I. Stage I corresponds to growth macroscopically limited to both ovaries, stage II when the growth involves local extension within the pelvis, stage III when the abdominal organs are involved and stage IV when extra-abdominal or liver metastases are present. In assessing the results of comparative trials it is important to show that the groups are comparable for stage, histology, and, as emphasized by Bush et al. (1977), the success of the initial operation to resect the tumour. In a comprehensive review of ovarian carcinoma Tobias & Griffiths (1976) have assessed the five-year survival rates at the various FIGO stages (Table 2). The five-year survival has varied in these cumulative figures, from 60% for stage I disease to less than 5~o in stage III and stage IV disease.

Time- and dose-dependent changes in ejection fraction after anthracycline therapy.

Abstract: Cardiac toxicity due to anthracycline therapy is dose related, and congestive failure is a major limiting factor to therapy. Radionuclide cardiac evaluation provides a sensitive noninvasive method for detecting changes in cardiac function. Fifteen patients receiving either doxorubicin or daunomycin were evaluated with radionuclide ejection fractions (EFrn). The data indicate that the EFrn can detect an acute depressant cardiac action of these drugs as early as 24 hr after drug administration. In addition, a cumulative or chronic cardiac depression was noted; cumulative dosage of doxorubicin or daunomycin correlated with a reduced EFrn (p less than 0.001). We conclude that (1) the EFrn can noninvasively detect significant changes in cardiac function at low cumulative doses of doxorubicin or daunomycin and (2) the EFrn may be useful in evaluating cardiac function in patients during doxorubicin or daunomycin therapy.

Study of the combined and separate administration of doxorubicin and coenzyme Q10 on mouse cardiac enzymes.

Abstract: Administration of an acutely toxic dose of doxorubicin to mice did not increase, but rather decreased the percent deficiency of coenzyme Q10 (CoQ10) as calculated according to the coenzyme-apoenzyme system principle. The date indicate that doxorubicin may occupy CoQ10-empty receptors on the apoenzyme, with or without some destruction of enzyme-menbrane structure close to the receptor. Data from mice receiving both CoQ10 and doxorubicin indicated that CoQ10 may protect against doxorubicin. CoQ10 alone corrected the pre-existing deficiency found in control mice.