Showing papers on "Doxorubicin published in 1978"

Effect of alpha-tocopherol on the cardiotoxicity of adriamycin in the rat.

Abstract: Adriamycin (ADR)-induced cardiomyopathy was studied in a rat model by means of electrocardiograms (ECGs), light microscopy, and determination of heart weight. Pretreatment with D-α-tocopherol (α-T) 24 hours prior to a high dose of ADR diminishes cardiotoxic effects, as judged by ECG changes, decreases in heart weight, and histologic changes. The response of an acute myeloid leukemia in a rat model to ADR was not affected by this pretreatment. The results provide evidence that α-T might be used to improve the therapeutic index of ADR. Chemicals/CAS: alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; cytarabine, 147-94-4, 69-74-9; doxorubicin, 23214-92-8, 25316-40-9; Doxorubicin, 23214-92-8; Vitamin E, 1406-18-4

Transport and Storage of Daunorubicin and Doxorubicin in Cultured Fibroblasts

Abstract: For elucidation of the mechanism behind the differences in cellular accumulation of daunorubicin and doxorubicin, the uptake and subcellular localization of these drugs were studied in cultured fibroblasts by cell fractionation techniques. Daunorubicin and doxorubicin accumulated to the same saturation level in nuclei, whereas the lysosomal concentration of daunorubicin always exceeded that of doxorubicin. No saturation of lysosomes could be achieved under the experimental conditions used. In both cellular storage pools, more of the drug was found when the cells had been incubated in a medium at pH 7.8 than after incubation at pH 6.9. Metabolic inhibitors enhanced the accumulation of both drugs under conditions under which most of the drug was stored in nuclei. On the other hand, low incubation temperature inhibited drug accumulation under conditions under which most of the drug was stored in lysosomes. The accumulation of N -acetyldaunorubicin markedly exceeded that of N -acetyldoxorubicin, although these derivatives were not stored in significant amounts in either nuclei or lysosomes. Our results support the hypothesis that transport of daunorubicin and doxorubicin across the plasma membrane occurs by a “leak and pump” system, the leak being inward diffusion of non-ionized drug molecules and the pump being an active efflux. Since daunorubicin is less polar than is doxorubicin, it can be assumed to diffuse faster across biological membranes, which should lead to a higher cytoplasmic steady-state level. On this basis a hypothesis is presented to explain the observed differences in cellular accumulation and subcellular distribution between daunorubicin and doxorubicin.

Changes of Granulopoiesis during and after Adjuvant Chemotherapy of Breast Cancer

Abstract: Adjuvant chemotherapy allows a study of the effects of cytotoxic drugs on natural human haematopoiesis We describe serial studies of granulopoiesis performed during and after intermittent adjuvant chemotherapy for breast cancer (adriamycin plus cyclophosphamide, given for six courses at monthly intervals) After drug administration, a sequential wave of depletion and regeneration through successive granulopoietic compartments was observed With repeated chemotherapy, moderate neutropenia developed, and the blood CFU-C pool size became progressively reduced After the sixth chemotherapeutic course, granulopoietic regeneration was delayed Following discontinuation of chemotherapy, a long-lasting (greater than 200 d) reduction of the blood CFU-C pool size, together with neutropenia and reduction of marrow segmented neutrophils, was observed, suggesting a defect of granulopoiesis with persistent granulopoietic hypoplasia In patients with expected long survival, residual bone marrow damage should be added to the list of potential late side effects of cytotoxic drug therapy

Failure of medullary carcinoma of the thyroid to respond to doxorubicin therapy

Abstract: We describe 3 patients with metastatic medullary carcinoma of the thyroid who were treated with doxorubicin hydrochloride (Adriamycin). Serum calcitonin was measured before and after doxorubicin therapy. Doxorubicin failed to arrest the progression of the disease in any of the patients. Although serum calcitonin levels dropped in 1 patient during therapy, they remained markedly elevated in all 3 patients. From the present series it appears that medullary thyroid carcinoma often does not have a response to doxorubicin.

An Apparently Effective Countermeasure for Doxorubicin Extravasation

Abstract: To the Editor.— Doxorubicin hydrochloride (Adriamycin) extravasation inevitably leads to local tissue damage. The development of tissue ulceration depends on the injection site. 1,2 Recently we treated a patient who was inadvertently given 40 mg of doxorubicin hydrochloride subcutaneously into the forearm. Immediately 5 ml of 8.4% sodium bicarbonate was intentionally infiltrated into the same area followed by 4 mg of dexamethasone (Decadron). Six weeks since the episode, there has been only minimal swelling and tenderness, without any erythema of the involved area. The use of corticosteroids for doxorubicin extravasation has been previously suggested. 2 One reason for adding the sodium bicarbonate is that the binding of doxorubicin to tissue is pH dependant. 3 Drastic transient local perturbation of pH would extinguish hydrogen bonding, inhibit the production of the cationic form of doxorubicin, and possibly prevent the formation of the DNA-doxorubicin complex. 3,4 This complex is probably the culprit in

Pulmonary edema associated with intravenous vinblastine.

Abstract: To the Editor.— A recent case demonstrated an association between the intravenous (IV) administration of vinblastine and the development of pulmonary edema. Report of a Case.— A 64-year-old woman is receiving chemotherapy for infiltrating duct carcinoma of the breast metastatic to bones. A breast mass was diagnosed in May 1972, with a subsequent right radical mastectomy. One of 24 axillary nodes was abnormal. Bony metastasis appeared in November 1974. She has been treated sequentially with estrogen, cryohypophysectomy, and combination chemotherapy (first with cyclophosphamide [Cytoxan], methotrexate, and fluorouracil; then doxorubicin hydrochloride [Adriamycin] and cyclophosphamide and recently with mitomycin and vinblastine sulfate). She has hypertension, which has been therapeutically controlled since 1969. The insidious onset of congestive heart failure developed in May 1977, consistent with doxorubicin toxicity (total dose, 400 mg/sq m). Doxorubicin therapy was discontinued, and she responded to digitalization and diuresis. She has remained well compensated with digoxin, hydrochlorothiazide (Hydrodiuril),

Adriamycin and 1‐(2‐Chlorethyl)‐3‐Cyclohexyl‐1‐Nitrosourea (CCNU) in the treatment of metastatic breast cancer

Abstract: Adriamycin every three weeks and CCNU every six weeks were given to thirty patients with metastatic breast carcinoma. Most patients had received prior chemotherapy. The overall response rate was 40%, with three patients obtaining complete remission. Survival was significantly prolonged in responders versus nonresponders. Three patients developed CNS metastasis while on treatment. Prior chemotherapy was a major factor in determining response rate; all patients without prior chemotherapy responded. The combination appears to be inferior to adriamycin alone in patients who have received prior chemotherapy.

Potentiation of the toxicity of adriamycin by propranolol.

Abstract: Both propranolol and adriamycin are biochemically known to inhibit mitochondrial CoQ10-enzymes of myocardial tissue in vitro. Both propranolol and adriamycin are clinically known to cause cardiotoxicity. At two dose levels of propranolol which caused no deaths to mice when administered alone, significant potentiation (p less than 0.01) of the lethality of adriamycin to mice was observed. These data, projected to the clinical situation, seem to contraindicate the administration of the beta-blocker, propranolol, for the hypertension of a cancer patient who is being treated with adriamycin.

Blockade of tissue uptake of the antineoplastic agent, doxorubicin.

Abstract: Myocardial uptake of doxorubicin (Adriamycin) and its inhibition by digoxin and propranolol were studied in paced, isolated perfused cat hearts using tritiated doxorubicin. Contractility was studied using a Walton-Brody strain gauge arch and its first derivative. Coronary blood flow was measured by collecting the effluent from the heart. The myocardial content of doxorubicin was 0.069 +/- 0.101 nmol/mg after 30 minutes. Combined administration of doxorubicin and digoxin reduced the myocardial content of doxorubicin to 0.025 +/- 0.010 nmol/mg (P less than .02). The combination increased contractility compared with doxorubicin alone and increased coronary blood flow compared with digoxin alone. The reduction in the myocardial content of digoxin by doxorubicin was not significant. Propranolol also reduced the myocardial uptake of doxorubicin (P less than .05) without changing coronary blood flow and without further reducing contractility. Thus, both propranolol and digoxin merit evaluation in preventing doxorubicin cardiotoxicity.

Biodistribution of Intravenously Injected [14C] Doxorubicin and [14C] Daunorubicin in Mice: Concise Communication

Abstract: [14C] doxorubicin (adriamycin) and [14C] daunorubicin (daunomycin) are cardiotoxic antibodies used in cancer therapy. These drugs were examined as possible agents for the measurement of regional myocardial blood flow. The antibiotics were injected intravenously into mice, which were then killed after various intervals. At a chemical dosage of 0.5 mg per kilogram, the content of the heart never exceeded 0.60% of the administered dose for doxorubicin and 0.55% for daunorubicin. The cardiotoxic effect of these drugs, therefore, is probably related to a specific sensitivity of the heart, rather than to an avid uptake of the drugs by the cardiac muscle. Further studies seem warranted, using a lower chemical dosage and higher specific activity.

Chemoresponsiveness of Moloney Sarcoma Virus-induced Osteosarcoma to Adriamycin in the Rat

Abstract: The chemoresponsiveness of a Moloney sarcoma virus-induced osteosarcoma in the rat to i.v. Adriamycin therapy was demonstrated by ( a ) prolongation of life span, ( b ) reduction in tumor size, and ( c ) morphological alterations of the neoplasm. Adriamycin was given to groups of osteosarcoma-bearing rats i.v. or i.p. at 2 mg/kg/week for 10 weeks, at 1 mg/kg/week for 10 weeks, and at 1 mg/kg on Monday, Wednesday, and Friday followed by a week of rest (repeated to a total of 10 injections). Rats receiving 1 mg/kg/week had the most consistent response to Adriamycin treatment, with a significant prolongation of life span from 40 through 95 days and a significant decrease in tumor diameter from 7 days through 50 days after the start of treatment. Other Adriamycin regimens also produced a significant increase in life span and a reduction in tumor size, compared to results with rats in the placebo group. Radiographic evaluation of osteosarcomas demonstrated an increased radiodensity with Adriamycin therapy, compared to a rapid proliferation and destruction of preexisting bone in the placebo group. Microscopic and ultrastructural evaluation of osteosarcomas following various intervals of Adriamycin revealed necrosis of tumor cells, fibroblastic proliferation, and mineralization of osteold matrix. Metastatic lesions in lung and sublumbar lymph node also were sensitive to Adriamycin therapy, as reflected by necrosis of tumor cells. Evidence of congestive heart failure and cardiomyopathy was observed in all groups of rats on Adriamycin chemotherapy. The sensitivity of the osteosarcoma-bearing New Zealand black rat to the antitumor and cardiomyopathic effects of Adriamycin provides an animal system for evaluation of the oncolytic activity of new analogs as well as their cardiotoxic potential.

Adjuvant chemotherapy in T3 bladder cancer.

Abstract: SIR,-I was interested to read your leading article on this subject (3 June, p 1436), especially that section in which you state that \"from the infrequency of reports of death during sleep apparently due to suffocation during a fit the hazard may be presumed rare-especially in comparison with the frequency of nocturnal fits in children. Even so, substitution of a firm pillow might be a wise safeguard.\" This statement is certainly contrary to the conclusions drawn by my colleague Dr H J A Longmore and myself in 1970, when three patients with grand mal epilepsy who had died by suffocation in their pillow were reported.' This article stimulated the reply from Dr C Worster-Drought2 on which was based the comment referred to above. Dr Worster-Drought had, during his 45 years as a neurologist in Harley Street, seen no such cases and considered them uncommon. My own view is that such tragic deaths are not so uncommon and that most of them occur in the home so that their frequency is not generally appreciated-certainly not by consultant neurologists. To emphasise the need for patients with grand mal epilepsy to use smother-proof pillows a further letter was written in 1973 describing two further cases which had occurred in Dumfriesshire within a 10-year period.:' Should this incidence be typical of the rest of the country this would mean that 20 cases would occur in Scotland each year-no negligible number. An article from Denmark4 helps to bear out my contention. The number of deaths in epilepsy was found to be increased in the fourth and fifth decades by 413 and 558,) respectively. From my own findings and from the fact that six other cases have come to my notice since the publication of our original article (the latest, reported in the Bury Times on 6 January this year, described an epileptic who had suffocated in his pillow during a fit, this time in hospital with the diagnosis verified at post-mortem examination) I would suggest, contrary to the statement in your leading article, that many deaths in younger epileptics do occur from suffocation during a fit.

[Survey of anthracyclines derivatives in haematology (author's transl)].

Abstract: Anthracyclines, such as daunorubicin (DNR), rubidazone (RBD) and adriamycin (ADR) are intercalating drugs used in cancer chemotherapy. They inhibit synthesis of DNA and RNA, break DNA and inhibit mitochondrial oxidative chain. Their antitumoral experimental activities depend upon type of drug, tumor and route of administration. After i.v. administration, the drug is present in all tissues except central nervous system. Its disappearance from the plasma is biphasic with a long terminal half life, justifying intermittent chemotherapy. Anthracyclines metabolism occurs mainly in liver micrososomes, and 90% metabolites are excreted in the bile. The main toxicity is cardiac, as a congestive heart failure which appears when a cumulated drug dose is overcome. In man only, a few derivatives have been studied, compounds with activity and no cardiotoxicity are still in research. Action of malignancies depends on type of derivative. We use DNR since 1967, it is a remarkable active drug in induction treatment of AML, it is the only active drug on acute promyelocytic leukemia, and it increases number of remissions in all of adult patients and severe forms of children ALL. Adriamycin (ADR) is active on solid tumors (osteosarcoma, breast and thyroid cancers) and lymphomas. With rubidazone (RBD) we obtain 2/3 of remissions in acute monoblastic leukemia, and it is easier to use than DNR and equally active on AML. RBD is also active on severe cases of lymphomas (lymphosarcomas and Hodgkin's disease). A new compound DEA 14 DNR seems interesting: experimental antitumor activity is high (compared to DNR, RBD and ADR) and it appears to possess activity on solid tumors in man.

African trials in chemotherapy of gastrointestinal cancer.

Abstract: Bleomycin either alone or in combination with radiotherapy was used in the treatment of 24 patients with non-resectable cancer of the oesophagus. Improvement in performance (swallowing) status was observed in 75% of patients, although only 19% were known to be alive after 1 year of follow-up. Patients with liver cancer were treated with adriamycin. The response rate was dose dependent and was 40% at best. Combination of adriamycin with other drugs did not improve the response rate. Intra-arterial adriamycin appears more efficacious and gave a response rate of 60%.