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PubMed1979

Quantitative models for growth inhibition of human leukemia cells by antitumor anthracycline derivatives.

A batch elution method with hydroxylapatite was developed to assay DNA damage by a set of antitumor anthracycline derivatives and was standardized with respect to the kinetics of unwinding, size of the alkaline unwinding unit, and fidelity of selective elution of single and double-stranded DNA. The method was applied to a study of a set of 10 antitumor anthracycline derivatives which inhibit growth of CCRF-CEM human leukemia cells over a range of potencies exceeding four orders of magnitude. The derivatives, including Adriamycin, daunorubicin, and carminomycin, vary in structure at C-4 and C-13, with substitutions at C-14 and N and stereochemical differences at C-4'. In a static model (fixed drug concentrations and incubation times), the potency [1/ID37 (concentration of agent that inhibits cell growth by 37%)] of nine of the ten derivatives may be expressed as functions of DNA damage (n), inhibition of thymidine incorporation (l), and drug retention (r): ID37 = Ka(r/l . n)kb, with a coefficient of correlation of greater than 0.99. A kinetic model with 4-demethoxydaunorubicin (varying concentrations and incubation times) was also described. Following initial uptake and a period of rapid loss after cells are washed free of excess drug, the change in agent concentration in the cells follows first-order kinetics. The cell index (cell number after 50 hr in drug-free growth medium/cell number after initial 2-hr exposure with drug) may be expressed linearly in terms of the kinetics of drug loss (coefficient of correlation, greater than 0.98), or as functions of 1/n (coefficient of correlation, greater than 0.958), 1/l . n (coefficient of correlation, greater than 0.963, or r/l . n (coefficient of correlation, greater than 0.963). These studies may be used to define a class of similarly acting anthracycline agents and to give some insight into the mechanism of action of the agents that fall within the class.

Antibiotics, Antineoplastic↗

PubMed1979

Effect of aeration efficiency and carbon source on the production of anthracyclines in Streptomyces galilaeus.

Biosynthesis of anthracyclines in Streptomyces galilaeus during submerged cultivation is considerably influenced by aeration and by the concentration of glucose in the medium. At higher values of oxygen absorption rate both the production of epsilon-pyrromycinone glycosides in the wild strain JA 3043 and its production mutant G-167 and accumulation of free epsilon-pyrromycinone in the blocked mutant G-162 were found to be higher; the production of 7-deoxyaglycones was lower in all strains. The studied strains differed in the rate of glucose consumption and in the ability to utilize starch for the biosynthesis of anthracyclines. A two-fold concentration of glucose in the medium resulted in the G-162 strain in an increase of the yield of epsilon-pyrromycinone by 120%. The production of glycosides in strain G-167 increased even after exhaustion of glucose from the medium and the amount of 7-deoxyaglycones simultaneously decreased.

Anti-Bacterial Agents↗

PubMed1979

Absence of anthracycline-induced degradation of nuclear DNA in Ehrlich ascites tumour cells.

The in vivo effects of anthracycline antibiotics on the integrity of Ehrlich ascites tumour cell DNA have been studied by sedimentation analysis of nuclear structures containing superhelical DNA in neutral sucrose gradients. These fast-sedimenting protein-DNA complexes may be released by gently lysing cells in solution containing non-ionic detergents and high NaCl concentrations (1.95 M). The supercoiled structure of DNA in these protein-DNA complexes is suggested by the characteristic sedimentation in the presence of intercalating agents. Apparently, no DNA damage could be detected in Ehrlich cells from 7-day-old tumours within 3 h after various doses of daunomycin (0.5--10 mg/kg of body wt.) were administered i.p. to mice. Sedimentation anomalies could not be observed even 15 or 30 h after administration of rtherapeutic doses of daunomycin or adriamycin. In contrast, at 30 min after administration to mice, therapeutic doses of bleomycin (2--8 mg/kg) caused extensive fragmentation of tumour cell DNA, which could be monitored as slowly sedimenting DNA structures (compared with the the control). Similarly, DNA damage could be induced by procarbazine at therapeutic doses. Exposure to bleomycin or procarbazine abolished the characteristic biphasic response to ethidium bromide. The absence of anthracycline-induced degradation of Ehrlich ascites tumour cell DNA is apparently in contrast with the DNA damage observed in L1210 tumour cells. These observations suggest that DNA damage is not a necessary condition for antitumour activity.

Animals↗

PubMed1978

Anthracycline antitumor antibiotic nucleic-acid interactions. Structural aspects of the daunomycin poly(dA-dT) complex in solution.

The helix-to-coil transition of the synthetic DNA poly(dA-dT) in the presence of the anthracycline antitumor antibiotic daunomycin has been investigated by high-resolution proton nuclear magnetic resonance (NMR) spectrocopy in 1 M salt solution. The dissociation of the complex, containing molar ratios of phosphate to daunomycin (Pi/drug) of 50, 25, 9 and 5, with increasing temperature can be monitored independently at the nucleic acid and the antibiotic resonances under conditions of fast exchange. The antibiotic complex formation shifts suggest that either ring B and/or C of the intercalated anthracycline chromophore of daunomycin overlaps with adjacent nucleic acid base pairs. Ultraviolet/visible melting studies of daunomycin complexes with a series of synthetic DNAs substituted with halogen atoms (Br, I) at position 5 of the pyrimidine ring suggest that intercalation of the antibiotic into poly(dA-dU) is not perturbed by bulky substituents at this position. A comparison of the melting curves for the daunomycin . poly(dA-dT) complex with an analog of the antibiotic where the NH3 + group is replaced by dimethylglycine demonstrates the important contributions of electrostatic interactions between the amino sugar and backbone phosphates to the stability of the complex in low salt solution. The ultraviolet/visible and NMR studies monitor biphasic melting transitions at the nucleic acid markers in the daunomycin . poly(dA-dT) complexes, Pi/drug = 50--9, so that antibiotic-free base-pair regions and those centered about bound daunomycin can be independently studied at the synthetic DNA level in solution.

Chemical Phenomena↗

PubMed1979

Laser flow cytometry and cancer chemotherapy: detection of intracellular anthracyclines by flow cytometry.

The intracellular distribution of important chemotherapeutic antibiotics belonging to the anthracycline group (e.g. adriamycin) can be detected by laser flow cytometry. The indirect method is based on the interference of these compounds with the binding of propidium iodide to the nuclear DNA. While in the direct method, the intracellular fluorescence of these antibiotics is excited and detected with a laser beam in a flow system. The present report demonstrates the use of these two methods for intracellular detection and quantitation of a number of important anthracyclines.

Animals↗

PubMed1978

Comparative ultrastructural studies of nucleoli of tumor cells treated with adriamycin and the newer anthracyclines, carminomycin and marcellomycin.

This study was designed to determine the effects of several antitimor anthracyclines, including Adriamycin and its analogs, carminomycin and marcellomycin, on the ultrastructure of nucleoli of Novikoff hepatoma cells. Adriamycin and carminomycin, which are structurally related, induce nucleolar segregation following the formation of conspicuous fibrillar centers. Marcellomycin did not induce formation of nucleolar fibrillar centers. Instead, numerous microspherules formed following treatment with marcellomycin; later complete nucleolar segregation developed. The microspherules were observed to be in various stages of extrusion from the nucleolar body. This microspherule "migration" appeared to be both time and drug concentration dependent. These results show that the rate and extent of nucleolar ultrastructural aberration may be related to structural differences of the various anthracyclines.

Animals↗

PubMed1979

Biochemical parameters of growth inhibition of human leukemia cells by antitumor anthracycline agents.

Ten antitumor anthracycline derivatives used in this study inhibit growth of a human leukemia cell line over a range of potencies exceeding four orders of magnitude. The agents vary from each other at C-4 and C-13, with stereochemical differences at C-4' and substitutions at C-14 and N. Drug retention, DNA damage, and inhibition of DNA synthesia are parameters used to express potency of the agents in a mathematic model. Estimates of DNA damage are sufficient, however, to describe growth inhibition by a single agent (4-demethoxydaunorubicin). It may be possible now to attempt to extend the model to predict therapeutic responses to a number of anthracyclines, thereby enhancing the clinical utility of this important class of agents.

Antibiotics, Antineoplastic↗

PubMed1978

Overview of cardiac pathology in relation to anthracycline cardiotoxicity.

A review is presented of cardiac pathologic changes associated with acute and chronic toxicity of anthracyclines. These changes consist of cardiac dilatation, degeneration and atrophy of the muscle cells, and interstitial edema and fibrosis. The degeneration of cardiac muscle cells is a complex phenomenon that involves the myofibrils, the nucleus, the mitochondria and the membrane systems of the T-tubules, the sarcoplasmic reticulum, and the intercellular junctions. The pathogenesis of these alteration is discussed in terms of the biochemical effects of anthracyclines.

Animals↗

PubMed1979

Reduction of anthracycline glycoside by NADPH--cytochrome P-450 reductase.

The in vitro degradation of the new antitumor anthracycline antibiotic, aclacinomycin-A, was studied using rat liver homogenate. In the presence of NADH or NADPH, the glycosidic bond at C-7 position of aclacinomycin-A was reductively cleaved to produce 7-deoxyaklavinone and 7-deoxyaklavinone dimer, MA144 E1. Subcellular fractionation indicated that most of the enzyme activity was present in the microsomal fraction and required anaerobic condition and NADPH. The purified enzyme reduced the glycosidic metabolites, MA144 M1 and MA144 N1, as well as aclacinomycin-A. The optimum pH for the anthracycline glycoside reductase reaction using aclacinomycin-A as substrate was 7.4. The enzyme was sigmoidally saturated with aclacinomycin-A and showed the concentration of 1.2 x 10(-4) M required for half maximal activity, and Km value of 7.7 x 10(-5) M for NADPH. The degradative pathway of aclacinomycin-A and its glycosidic metabolites was discussed.

Anaerobiosis↗

PubMed1979

Anthracycline antibiotic pharmacology and metabolism.

The anthracycline antibiotics show evidence of numerous interactions with cellular components and participation in several metabolic pathways. Small structural changes in the antibiotic molecule can produce major changes in intracellular localization and interaction. To date, we find that all of the anthracycline antibiotics form free radical intermediates through the catalysis of microsomal and nuclear electron-transport machinery. NADPH cytochrome P-450 reductase catalyzes the free radical formation. The free radical intermediates ("site-specific free radicals") may be causative of both toxicity and pharmaceutic action. The free radical intermediates degrade nonenzymatically to 7-deoxyaglycone metabolites which prove the existence of the free radical in vivo.

Animals↗

PubMed1979

Experimental evaluation of anthracycline analogs.

This review summarizes the preclinical tests conducted to date for experimental evaluation of new anthracycline analogs. Most of the data are derived from the experience at the Istituto Nazionale Tumori, Milan, Italy, at the National Cancer Institute, Bethesda, Md, and at the Farmitalia Research Laboratories, Nerviano, Italy. In vitro cytotoxicity tests are useful for determining the doses to be used in vivo. Antitumor activity tests in mice can be divided into different stages. P388 and L1210 leukemias are generally used in primary screening; the value of adding L1210 leukemia is briefly discussed. Other experimental tumors adopted include disseminated leukemia and transplanted solid tumors. The importance of the route and schedule of treatment is stressed. Drugs should be administered iv in the case of solid tumors, and the schedule of treatment can be adjusted according to the pharmacokinetic properties of the new analog, when these are known. If possible, the parent compound and the new analog should be dissolved in the same solvents. In the toxicity tests, cardiac toxicity deserves particular attention. Until now, the only experimental model in which a number of new anthracyclines have been tested is the rat model proposed by Zbinden. A comparison between cardiotoxicity data obtained in such models and antitumor data obtained in mice shows that cardiac toxicity can be dissociated from the antitumor activity. Knowledge of pharmacokinetic properties of new analogs is of importance for selecting the schedules of treatment and for explaining selective toxic effects.

Animals↗

PubMed1979

The interval-force relationship: a technique for evaluating the cardiac toxicity of anthracycline analogs.

The most serious side effect of the anthracycline derivatives is dose-related cardiac toxicity induced during repeated administration. An in vitro method is described which assesses the interval-force relationship in evaluating the contractility of the rat and rabbit heart. Repeated administration of Adriamycin resulted in a progressive decrease in contractility which correlated closely with the cumulative dose administered. This model offers a reliable method to evaluate the effect of new anthracycline analogs on the heart and to study the potential of other drugs or agents to protect against cardiac toxicity.

Animals↗

PubMed1979

[Rapid change in the dynamics of antibody-forming cells under the influence of a single injection of various anthracyclines].

The dynamics of the titers and number of the antibody forming cells was studied within 26 hours after a single injection of anthracycline to immunized animals at various phases of the immune response. The specificity of the "rapid" effect of anthracyclines suggests that the low differentiated precursors of the antibody forming cells are the main target for the rubomycin effect and the immune competent cells in the state of multiplication and differentiation under the effect of the antigen are the main target for the carminomycin effect. The study was performed with noninbred mice immunized with sheep red cells.

Animals↗

PubMed1977

Antitumor activity of new anthracycline antibiotics, aclacinomycin-A and its analogs, and their toxicity.

New anthracycline antibiotics have been isolated from the culture of Streptomyces galilaeus MA144-M1. Among 14 anthracycline compounds, aclacinomycin-A showed the strongest activity in inhibiting leukemia L-1210 and had lower toxicity than others. Antitumor activity of aclacinomycin-A against leukemia L-1210 and P-388, solid sarcoma-180, and lymphosarcoma 6C3HED was examined in comparison with adriamycin and daunomycin. Aclacinomycin-A showed the same degree of activity against leukemia L-1210 and P-388, when administered intraperitoneally, as daunomycin and somewhat less than adriamycin. In oral administration, aclacinomycin-A also exhibited a significant activity on leukemia L-1210. The degree of inhibition of the growth of sarcoma-180 and 6C3HED lymphosarcoma transplanted subcutaneously by aclacinomycin-A was almost the same as that of adriamycin and daunomycin, although the optimal dose was about twice more than adriamycin. Acute cardiotoxicity of aclacinomycin-A by a test using hamsters was more than 10 times lower than that of adriamycin.

Aclarubicin↗

PubMed1978

Clinical spectrum of anthracycline antibiotic cardiotoxicity.

Anthracycline derivatives may produce early or late cardiotoxic reactions in man. Early effects include: (a) pericarditis-myocarditis which can affect patients with no previous history of cardiac disease and which carries a high mortality rate ( approximately 20%); (b) left ventricular dysfunction which may lead to clinically significant heart failure in patients with limited cardiac reserve; and (c) arrhythmias, the most common of which is sinus tachycardia. Symptomatic supraventriclar tachycardia, heart block, and ventricular arrhythmias can occur, however, and may reflect primary effects on cardiac muscle or the conduction system. Late effects of anthracyclines are directly related to the degree of associated myocyte damage and include subclinical left ventricular dysfunction and overt heart failure. The implications for prognosis and further treatment are discussed for each of these entities and a common pathogenetic mechanism is proposed.

Adolescent↗

PubMed1978

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

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.

Adult↗

PubMed1978

Preliminary results of a phase II trial of aclacinomycin in acute leukaemia and lymphosarcoma. An oncostatic anthracyclin that is rarely cardiotoxic and induces no alopecia.

A phase II trial of which preliminary results are available for 22 patients indicates that aclacinomycin applied in a continuous modality induced complete and partial remission in four of nine patients with acute lymphoid leukaemia that was resistant to all previously available drugs, and in four of eight patients with stage V lymphosarcoma (leukaemic). Bone-marrow toxicity was the major side-effect. Only one patient of 20 suffered from cardiac toxicity; no one had alopoecia. This very low incidence of myocardial lesions and the absence of hair loss had been predicted, respectively, by our electron microscope study of the myocardium and the light electron microscope study of the skin of golden hamsters [7], a test that detects frequent severe myocardium and skin toxicities for adriamycin and some anthracyclin analogues such as detorubicin, which was found to be toxic in a high percentage of patients in a clinical trial conducted by the E.O.R.T.C. Clinical Screening Group [8].

Acute Disease↗

PubMed1978

Interaction of anthracyclines with DNA and chromosomes.

Daunomycin and adriamycin were previously found to produce Q-like banding patterns on chromosomes. The interaction of several anthracyclines with both natural and synthetic DNAs and chromosomes has been investigated in more detail. Daunomycin fluorescence is almost completely quenched by natural DNAs with varying base composition from 31 to 72% G-C and by the alternating polymer poly-d(G-C).poly-d(G-C). In contrast, daunomycin fluorescence is quenched by only 50% when the dye interacts with synthetic A-T polymers. Thus, differential quenching of daunomycin fluorescence can account for the production of bright bands at contiguous A-T sequences along the chromosome. Slight differences in fluorescence quenching between the repeating and homopolymeric A-T duplex DNAs were observed which can be attributed to differences in affinity of daunomycin for these DNAs. The aminosugar moiety of daunomycin, daunosamine, increases the binding of daunomycin to DNA and also enhances chromosome banding.--Nogalamycin, which displays no differential quenching with the different DNAs in solution, also fails to produce bands on chromosomes.--These findings suggest that non-random nucleotide sequence arrangements along the chromosome are a basic determinant for dye interaction to produce the observed banding patterns. Specific banding procedures may determine the accessibility of these sites within the chromosomal DNA.

Animals↗