aclarubicin and Lung-Neoplasms

The nuclear enzyme DNA topoisomerase II is a major target for antineoplastic agents. All topoisomerase II-directed agents are able to interfere with at least one step of the catalytic cycle. Agents able to stabilize the covalent DNA topoisomerase II complex (also known as the cleavable complex) are traditionally called topoisomerase II poisons, while agents acting on any of the other steps in the catalytic cycle are called catalytic inhibitors. Thus, catalytic topoisomerase II inhibitors are a heterogeneous group of compounds that might interfere with the binding between DNA and topoisomerase II (aclarubicin and suramin), stabilize noncovalent DNA topoisomerase II complexes (merbarone, ICRF-187, and structurally related bisdioxopiperazine derivatives), or inhibit ATP binding (novobiocin). Some, such as fostriecin, may also have alternative biological targets. Whereas topoisomerase II poisons are used solely for their antitumor activities, catalytic inhibitors are utilized for a variety of reasons, including their activity as antineoplastic agents (aclarubicin and MST-16), cardioprotectors (ICRF-187), or modulators in order to increase the efficacy of other agents (suramin and novobiocin). In this review, the mechanism and biological activity of different catalytic inhibitors is described, with emphasis on therapeutically used compounds. We will then discuss future development and applications of this interesting class of compounds.

Topics: Aclarubicin; Antineoplastic Agents; Breast Neoplasms; DNA Topoisomerases, Type II; Enzyme Inhibitors; Female; Hematologic Neoplasms; Humans; Lung Neoplasms; Male; Piperazines; Prostatic Neoplasms; Sarcoma; Topoisomerase II Inhibitors

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Carubicin; Daunorubicin; Doxorubicin; Female; Glycosides; Hodgkin Disease; Humans; Leukemia; Lung Neoplasms; Lymphoma; Naphthacenes; Ovarian Neoplasms; Sarcoma

To determine the efficacy of aclarubicin hydrochloride in local control of malignant pericardial effusion, the authors carried out a trial of pericardial drainage with local administration of this agent in five patients, whose effusions had produced cardiac tamponade. All patients were women, and their primary cancers, all initially treated surgically, had arisen in the breast (two patients), or lung (three patients). Mean patient age was 54.2 years (range, 43-62). In four patients, improvement permitted removal of the drainage catheter. Two patients (40%) had a complete remission of the malignant pericardial effusion. The other three patients were difficult to evaluate because nonpericardial metastases limited their survival. All patients, however, showed disappearance of malignant cells from the pericardial sac with no cytopathologically demonstrable recurrence. In our few patients, intrapericardial aclarubicin appeared to be highly effective against malignant pericardial effusion.

Topics: Aclarubicin; Adult; Antineoplastic Agents; Breast Neoplasms; Cardiac Tamponade; Catheterization; Drainage; Female; Humans; Injections, Intralesional; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Pericardial Effusion; Treatment Outcome

Topics: Aclarubicin; Adult; Aged; Carcinoma, Small Cell; Drug Administration Schedule; Drug Evaluation; Drug Resistance; Female; Humans; Lung Neoplasms; Male; Middle Aged; Recurrence

Topics: Aclarubicin; Adenocarcinoma; Adult; Aged; Antibiotics, Antineoplastic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Middle Aged; Naphthacenes

Aclacinomycin-A (ACLA-A), the new anthracycline antibiotic that produces substantially less cardiotoxicity relative to doxorubicin, was evaluated in a phase II trial for advanced large cell and adenocarcinoma of the lung patients. Twenty-three patients with measurable disease were entered into the trial and received ACLA-A in doses of a weekly infusion of 65 mg/m2 and 85 mg/m2. Eighteen patients were evaluable for response and toxicity. Two patients were evaluable for toxicity only, one died before completion of a full course of therapy, and two did not receive the drug. There were no complete or partial remissions in this study. Three patients had disease stabilization for a median of 10 weeks (range 6-17). Toxicity was mainly hematologic. Nausea and vomiting were moderate. ACLA-A, in the dose schedules used, appears to have no activity in large cell and adenocarcinoma of the lung.

Topics: Aclarubicin; Adenocarcinoma; Adult; Aged; Carcinoma, Small Cell; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Infusions, Parenteral; Leukopenia; Lung Neoplasms; Male; Middle Aged; Naphthacenes; Nausea; Thrombocytopenia; Vomiting

Topics: Aclarubicin; Adult; Aged; Aziridines; Azirines; Benzoquinones; Brain Neoplasms; Carcinoma, Bronchogenic; Drug Evaluation; Female; Humans; Infusions, Parenteral; Lung Neoplasms; Male; Middle Aged; Naphthacenes; Random Allocation

Topics: Aclarubicin; Aged; Anaphylaxis; Anthraquinones; Antineoplastic Combined Chemotherapy Protocols; Aziridines; Benzoquinones; Drug Evaluation; Female; Hematologic Diseases; Humans; Infusions, Parenteral; Lung Neoplasms; Male; Middle Aged; Mitoxantrone; Naphthacenes

In this study, long-circulating Arg-Gly-Asp (RGD)-modified aclacinomycin A (ACM) liposomes were prepared by thin film hydration method. Their morphology, particle size, encapsulation efficiency, and in vitro release were investigated. The RGD-ACM liposomes was about 160 nm in size and had the visual appearance of a yellowish suspension. The zeta potential was -22.2 mV and the encapsulation efficiency was more than 93%. The drug-release behavior of the RGD-ACM liposomes showed a biphasic pattern, with an initial burst release and followed by sustained release at a constant rate. After being dissolved in phosphate-buffered saline (pH 7.4) and kept at 4°C for one month, the liposomes did not aggregate and still had the appearance of a milky white colloidal solution. In a pharmacokinetic study, rats treated with RGD-ACM liposomes showed slightly higher plasma concentrations than those treated with ACM liposomes. Maximum plasma concentrations of RGD-ACM liposomes and ACM liposomes were 4,532 and 3,425 ng/mL, respectively. RGD-ACM liposomes had a higher AUC0-∞ (1.54-fold), mean residence time (2.09-fold), and elimination half-life (1.2-fold) when compared with ACM liposomes. In an in vivo study in mice, both types of liposomes inhibited growth of human lung adenocarcinoma (A549) cells and markedly decreased tumor size when compared with the control group. There were no obvious pathological tissue changes in any of the treatment groups. Our results indicate that RGD-modified ACM liposomes have a better antitumor effect in vivo than their unmodified counterparts.

Topics: Aclarubicin; Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antibiotics, Antineoplastic; Area Under Curve; Cell Line, Tumor; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Stability; Half-Life; Injections, Intravenous; Lipids; Liposomes; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Oligopeptides; Particle Size; Rats; Solubility; Tumor Burden; Xenograft Model Antitumor Assays

Current evidence has suggested the possible involvement of ROS as signaling messengers in IL-1beta- or LPS-induced gene expression. We previously reported that both IL-1beta and LPS induce uPA in RC-K8 human lymphoma cells. Here, we provide evidence that ROS-generating anthracycline antibiotics, including doxorubicin and aclarubicin, upregulate uPA expression in 2 human malignant cell lines, RC-K8 and H69 small-cell lung-carcinoma cells. Both doxorubicin and aclarubicin markedly increased uPA accumulation in RC-K8- and H69-conditioned medium in a dose-dependent manner. In each case, maximal induction was observed at a sublethal concentration, i.e., at a concentration where cell growth was slightly inhibited. Both doxorubicin and aclarubicin increased uPA mRNA levels, and induction in each case reached the maximal level 9 hr after stimulation. Doxorubicin barely changed the half-life of uPA mRNA and activated uPA gene transcription. Antioxidants such as NAC and PDTC inhibited doxorubicin-induced uPA mRNA accumulation. Microarray analysis, using Human Cancer CHIP version 2 (Takara Shuzo, Kyoto, Japan), in which 425 human cancer-related genes were spotted on glass plates, revealed that uPA is 1 of 3 genes that were clearly upregulated in H69 cells by doxorubicin stimulation. These findings suggest that the anthracycline induces uPA in human malignant cells by activating gene transcription in which ROS may be involved. Therefore, by upregulating uPA expression, the anthracycline may influence many biologic cell functions mediated by the uPA/plasmin system.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Antioxidants; Blotting, Northern; Cell Nucleus; Cycloheximide; Dactinomycin; Dose-Response Relationship, Drug; Doxorubicin; Humans; Lung Neoplasms; Lymphoma; Oligonucleotide Array Sequence Analysis; Protein Synthesis Inhibitors; RNA, Messenger; Time Factors; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator

A 46-year-old woman had undergone a mastectomy in 1994, and metastases to the lung, bones and liver were detected in 1998. Brain metastases were detected later. Chemotherapy consisting of docetaxel, aclarubicin and UFT was administered, and image diagnosis revealed that CR was achieved. The chemotherapy was continued on a long-term basis, both as an inpatient and outpatient. The total administered doses have reached 2,000 mg of docetaxel and 1,000 mg of aclarubicin. The CR is being maintained as of this writing, 2 years and 4 months after the detection of the metastases. The patient's course continues to be monitored.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Docetaxel; Drug Administration Schedule; Drug Combinations; Female; Humans; Liver Neoplasms; Lung Neoplasms; Middle Aged; Paclitaxel; Taxoids; Tegafur; Uracil

The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, is appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCL nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the alpha and the beta isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt-and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types: etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.

Topics: Aclarubicin; Blotting, Western; Diterpenes; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Etoposide; Humans; Lung Neoplasms; Razoxane; Tumor Cells, Cultured

In previous studies, we found that VP-16 (etoposide) induced cytotoxicity and protein-concealed strand break formation was prevented in a small cell lung cancer (SCLC) cell line, when the cells were incubated with aclarubicin prior to treatment with VP-16. In the present work, we studied the effect of adding aclarubicin to the cell suspension after VP-16. In a clonogenic assay, we found that the cytotoxicity induced by VP-16 in SCLC cells was inhibited when cells were postincubated with aclarubicin. The addition of aclarubicin at any time in relation to VP-16 was able to stop further cytotoxicity induced by the topoisomerase II (topo-II) targeting drug. Aclarubicin was also found to antagonize the cytotoxicity induced by VM-26 (teniposide), and m-AMSA. With the alkaline elution technique we found that postincubating the cells with aclarubicin inhibited VP-16-induced DNA strand break formation. In an in vitro system with purified topo-II and naked DNA we likewise found, that postincubation with aclarubicin prevented VP-16 induced cleavage. In the same in vitro system, also baseline cleavage induced by topo-II was inhibited when aclarubicin was present. Importantly, aclarubicin exerted the antagonism to topo-II targeting drugs both when administered prior to and after the topo-II targeting agents. Thus, our data suggest that sequential rather than simultaneous administration of aclarubicin and topo-II targeting agents may be superior with respect to net-cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aclarubicin; Animals; Carcinoma, Small Cell; DNA Damage; DNA, Neoplasm; Etoposide; Humans; Lung Neoplasms; Mice; Time Factors; Topoisomerase II Inhibitors; Tumor Cells, Cultured; Tumor Stem Cell Assay

The following presents 6 cases of therapy related leukemia (TRL) along with discussion of their clinical features in comparison with those previously reported in Japan. Common primary malignancies were mammalian cancer, lung cancer and malignant lymphoma in both groups. It was observed that, 1) average age was higher (68 years), 2) average latent period from primary malignancy to leukemia was longer (10 years), particularly in patients treated solely with radiation, 3) in 4 out of 6 patients (67%) karyotype analysis of leukemia cells showed normal results, but in one case previously administered etoposide, translocation involving 15q+, 17q- was noted, and 4) the CR ratio in our cases was 83%; half the cases are still alive at 10 months of follow-up, while in previously reported cases the CR ratio was 41%, and the median survival time was 12 months according to Kaplan-Meier analysis. Although poor response to conventional chemotherapy has been reported in TRL patients, the present data indicated TRL in some cases to achieve complete response and long-term survival. Aggressive chemotherapy should be considered for such patients.

Topics: Aclarubicin; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Daunorubicin; Female; Humans; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms, Second Primary; Survival Rate

In contrast to the classic anthracyclines (doxorubicin and daunorubicin), aclarubicin (ACLA) does not stimulate topoisomerase II (topo II) mediated DNA-cleavage. This distinction may be important with respect to topo II-related drug resistance, and the aim of this study was to clarify drug-structures responsible for this difference. Various ACLA analogs were tested for: (a) interaction with purified topo II, (b) induction of DNA cleavage in cells, (c) cellular uptake and (d) cytotoxicity. A remarkable distinction was seen between analogs containing the chromophore aklavinone (AKV) (e.g. ACLA) which have a carboxymethyl group (COOCH3) at C-10 and drugs with a beta-rhodomycinone (RMN) chromophore with hydroxyl groups at C-10 and at C-11. Thus, RMN-containing analogs, including the aglycone RMN itself, effectively stimulated topo II-mediated DNA cleavage. In contrast, AKV-containing drugs inhibited DNA cleavage and antagonized cytotoxicity mediated by RMN-containing drugs. In OC-NYH/VM cells, exhibiting multidrug resistance due to an altered topo II phenotype (at-MDR), cross-resistance was only seen to the RMN-containing drugs whereas no cross-resistance was seen to the non-DNA cleaving AKV-containing compounds. Thus, our data show that one domain in the anthracycline is of particular importance for the interaction with topo II, namely the positions C-10 and C-11 in the chromophore, and further that at-MDR was circumvented by a COOCH3 substitution at position C-10. These findings may provide guidance for the synthesis and development of new analogs with activity in at-MDR cells.

Topics: Aclarubicin; Animals; Anthracyclines; Antibiotics, Antineoplastic; Carcinoma, Small Cell; DNA Damage; DNA Topoisomerases, Type II; DNA, Neoplasm; Drug Interactions; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Leukemia L1210; Lung Neoplasms; Mice; Naphthacenes; Stimulation, Chemical; Structure-Activity Relationship; Topoisomerase II Inhibitors; Tumor Cells, Cultured

Anthracyclines possessing either a 9-alkyl modification in the A-ring of the tetracyclic aglycone and/or specific changes to the amino sugar moiety retain effective cytotoxic activity against multidrug resistant (MDR) cell lines. To obtain a better understanding of the structural features responsible for this potentially valuable behaviour, we used the MTT tetrazolium dye reduction assay to calculate resistance factors (RF = the ratio of ID50 for the drug-resistant line to that for the parental line) for the EMT6/P mouse mammary tumour and its MDR variant EMT6/AR1.0, and the H69/P human small cell lung cancer line and its MDR counterpart H69/LX4. Both MDR lines exhibit marked resistance to doxorubicin, MDR 1 gene amplification, hyperexpression of the membrane P-glycoprotein and reduced drug accumulation. RF values for doxorubicin were 34 and 131 in the EMT6 and H69 cell line pairs, respectively. The 9-alkyl-substituted anthracyclines were confirmed as having RF values 9- to 15-fold lower than those for doxorubicin. The 9-ethyl analogues Ro 31-1966 (RF for EMT6 2.2, RF for H69 4.7) and Ro 31-1749 (RF for EMT6 3.9, RF for H69 9.5) were superior to the previously studied 9-methyl analogue Ro 31-1215 (RF for EMT6 8.1 RF for H69 12.4). A clear trend for RF values to decrease with increasing 9-alkyl chain length was also noted in the structurally more complex aclacinomycin series. For example, 13-methyl-aclacinomycin (RF for EMT6 1.0, RF for H69 2.2) featuring a 9-isopropyl moiety was superior to the 9-alkyl-containing aclacinomycin A (RF for EMT6 4.7, RF for H69 5.8), and this was in turn more effective than the 9-methyl analogue sulfurmycin A (RF for EMT6 6.4, RF for H69 14.2). The trisaccharide moiety was not an essential feature for activity against MDR lines in the aclacinomycins, as shown by the low RF value with aklavine (RF for EMT6 2.1, RF for H69 2.5). However, a small change in one of the sugar moieties of aclacinomycin A, as in marcellomycin, resulted in a considerable increase in RF values (RF for EMT6 18.5, RF for H69 25.3). The complex anthracyclines AD 32 (RF for EMT6 6.5, RF for H69 11.7) and particularly tetrahydropyranyl-doxorubicin (RF for EMT6 1.4, RF for H69 3.2) were effective against MDR lines.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Aclarubicin; Animals; Carcinoma, Small Cell; Doxorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Structure-Activity Relationship; Tumor Cells, Cultured

A novel anthracycline antibiotic, siwenmycin, isolated from the culture of Streptomyces galilaeus var. siwenesis, was examined for its antitumor activities against P388, K562, B16-F10, HeLa, HEp-2 and Lewis lung carcinoma cell lines. The results showed that siwenmycin was effective against P388, K562, HeLa and HEp-2 tumor cell lines in vitro, and significantly inhibited the growth of the Lewis lung carcinoma cell line in vivo. Siwenmycin could also suppress spontaneous and artificial pulmonary metastases of B16-F10 and Lewis lung carcinoma cell lines in C57BL/6 mice. The inhibitory effect of siwenmycin on spontaneous pulmonary metastasis of Lewis lung carcinoma in C57BL/6 mice was even stronger than that of adriamycin (ADM), which is, at present, commonly used in clinical practice. Furthermore, the double-labeling test used in this study has verified that siwenmycin can inhibit cellular RNA synthesis at about one tenth the concentration required to inhibit DNA synthesis to the same degree, indicating that the antitumor mechanism of siwenmycin also differs from that of ADM. The acute toxicity of siwenmycin was very low, and it was as effective in vivo as in vitro, suggesting that this newly found antibiotic should be studied for possible clinical antitumor applications.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; DNA, Neoplasm; Doxorubicin; HeLa Cells; Humans; Injections, Intraperitoneal; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred Strains; Mitolactol; Mitomycins; Neoplasm Metastasis; RNA, Neoplasm; Tumor Cells, Cultured

The effect of combinations of the anthracyclines aclarubicin and daunorubicin was investigated in a clonogenic assay using the human small cell lung cancer cell line OC-NYH and a multidrug-resistant (MDR) murine subline of Ehrlich ascites tumor (EHR2/DNR+). It was found that the cytotoxicity of daunorubicin in OC-NYH cells was antagonized by simultaneous exposure to nontoxic concentrations of aclarubicin. Coordinately, aclarubicin inhibited the formation of daunorubicin-induced protein-concealed DNA single-strand breaks and DNA-protein cross-links in OC-NYH cells when assayed by the alkaline elution technique. Aclarubicin had no influence on the accumulation of daunorubicin in these cells. In contrast, the accumulation of daunorubicin in EHR2/DNR+ cells was enhanced by more than 300% when the cells were simultaneously incubated with the MDR modulator verapamil, aclarubicin, or the two agents combined. Yet the cytotoxicity of daunorubicin was potentiated significantly only by verapamil. The increased cytotoxicity of daunorubicin in the presence of verapamil was completely antagonized when aclarubicin was used together with the MDR modulator. Finally, the effect of daunorubicin on the DNA cleavage activity of purified topoisomerase II in the presence and absence of aclarubicin was examined. It was found that daunorubicin stimulated DNA cleavage by topoisomerase II at specific DNA sites. The addition of aclarubicin completely inhibited the daunorubicin-induced stimulation of DNA cleavage. Taken together, these data indicate that aclarubicin-mediated inhibition of daunorubicin-induced cytotoxicity is due mainly to a drug interaction with the nuclear enzyme topoisomerase II. This antagonism at the nuclear level explains why aclarubicin is a poor modulator of daunorubicin resistance even though aclarubicin is able to increase the intracellular accumulation of daunorubicin in a MDR cell line.

Topics: Aclarubicin; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ehrlich Tumor; Carcinoma, Small Cell; Colony-Forming Units Assay; Daunorubicin; DNA; DNA Damage; DNA Replication; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Drug Antagonism; Humans; In Vitro Techniques; Lung Neoplasms; Mice; Verapamil

Two new experimental models of transplantable mouse sarcoma 180 were developed in ICR mice in order to examine the optimum transplantation sites and methods. The cervicodorsal hypoderm was evaluated as the best transplantation site for mouse sarcoma 180 among seemingly usable transplantation sites such as groin, armpit, cervicodorsal, abdominal and lumbodorsal hypoderms by hypodermic transplantation. In addition, the lung transplantation model was established by monitoring the survival period as a reliable parameter for evaluation of anti-tumor effects.

Topics: Aclarubicin; Animals; Antineoplastic Agents; Daunorubicin; Disease Models, Animal; Doxorubicin; Lung Neoplasms; Male; Mice; Mice, Inbred ICR; Neoplasm Transplantation; Sarcoma 180; Skin Neoplasms; Specific Pathogen-Free Organisms

The intramolecular combination of 9-alkyl substitution in the anthracycline A-ring plus incorporation of the amino group of the daunosamine sugar within a morpholinyl ring led to the retention of almost complete activity against P-glycoprotein positive, multidrug resistant variants of a mouse mammary tumour line and a human small cell lung cancer line. Resistance factors were close to unity. These structural elements may prevent efflux by the P-glycoprotein multidrug transporter. The use of 9-alkyl, morpholinyl anthracyclines with resistance circumvention properties may have clinical application.

Topics: Aclarubicin; Adjuvants, Immunologic; Animals; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Small Cell; Doxorubicin; Drug Resistance; Humans; Lung Neoplasms; Mammary Neoplasms, Experimental; Membrane Glycoproteins; Mice; Neoplasm Proteins; Tumor Cells, Cultured

The effect of combinations of the anthracycline aclarubicin and the topoisomerase II targeting drugs 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyra noside) (VP-16) and 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) was investigated in a clonogenic assay. The cytotoxicity of VP-16 was almost completely antagonized by preincubating cells with nontoxic concentrations of aclarubicin. The inhibition of cytotoxicity was not seen when the cells were exposed to aclarubicin after exposure to VP-16. The inhibition was significant over a wide range of aclarubicin concentrations (3 nM to 0.4 microM), above which the toxicity of aclarubicin became apparent. A similar effect was seen on the toxicity of m-AMSA. In contrast to aclarubicin, preincubation with Adriamycin did not antagonize the effect of VP-16. With purified topoisomerase II and naked DNA, aclarubicin did not stimulate the formation of cleavable complexes between topoisomerase II and DNA. Aclarubicin concentrations above 1 microM inhibited the baseline formation of cleavable complexes elicited with the enzyme alone. Low (1 to 10 nM) aclarubicin concentrations increased the formation of cleavable complexes obtained with VP-16 and m-AMSA; however, at aclarubicin concentrations above 1 microM an antagonistic effect was obtained. In cells, the m-AMSA- and VP-16-induced, protein-concealed DNA strand breaks were completely inhibitable by aclarubicin preincubation with no synergic dose levels. Our results suggest that aclarubicin inhibits topoisomerase II-mediated DNA cleavage. This inhibition could represent the mechanism of action of the drug and explain the lack of cross-resistance to the classical anthracyclines. The observed antagonism could have consequences for scheduling of aclarubicin with topoisomerase II-active anticancer drugs.

Topics: Aclarubicin; Amsacrine; Carcinoma, Small Cell; Cell Survival; DNA Damage; DNA, Neoplasm; Doxorubicin; Etoposide; Humans; Lung Neoplasms; Topoisomerase II Inhibitors; Tumor Cells, Cultured

The cytotoxicity anti-tumour intercalating agents such as the anthraquinone mitoxantrone is thought to relate to DNA binding and the trapping of DNA topoisomerase II complexes on cellular DNA. We have studied the uptake, nuclear location, DNA binding mode and DNA damaging capacity of mitoxantrone in a small cell lung carcinoma cell line (NCI-H69) compared with an in vitro-derived variant subline (NCI-H69/LX4) that exhibits "classical" multi-drug resistance (MDR). Variant cells maintained under doxorubicin selection showed reduced RNA levels that returned to control values within 7 days of growth under non-selective conditions. Variant cells released from selection stress showed resistance to DNA cleavage by doxorubicin, mitoxantrone, 4'-epidoxorubicin, 4'-deoxy-doxorubicin but reduced resistance to aclacinomycin A and a 9-alkyl substituted anthracycline in broad agreement with the cross-resistance patterns for cytotoxicity. Mitoxantrone treated NCI-H69 cells were found to accumulate DNA-protein crosslinks during a 4 hr post-treatment incubation period whereas variant cells maintained depressed levels of crosslinking. There was no apparent abnormality in the availability or drug sensitivity of topoisomerase II assayed in crude nuclear extracts of NCI-H69/LX4 cells. Whole cell uptake of radiolabelled mitoxantrone was depressed (50%) in NCI-H69/LX4 compared with NCI-H69, whereas assessment of nuclear-bound drug in individual cells by a fluorescence quenching technique showed at least a 10-fold greater level of target protection. The quenching results provide evidence of a high affinity, saturable mode of drug binding, favoured at low drug concentrations, that correlated with DNA cleavage capacity. We propose that the cytotoxic action of mitoxantrone is dependent upon a restricted and persistent form of binding to DNA that favours the long-term or progressive trapping of topoisomerase II complexes.

Topics: Aclarubicin; Carcinoma, Small Cell; Cell Survival; DNA Damage; DNA Topoisomerases, Type II; DNA, Neoplasm; Doxorubicin; Drug Resistance; Enzyme Induction; Humans; Intercalating Agents; Lung Neoplasms; Mitoxantrone; Tumor Cells, Cultured

The sensitivity of eight cell lines established from treated and untreated patients with small cell carcinoma of the lung (SCCL) was tested in the clonogenic assay with 1 h and continuous exposure to aclarubicin (ACLA), adriamycin (ADR), daunorubicin (DAU) and mitoxantrone (MITO). The sensitivity to ADR, DAU and MITO covariated, and varied with a factor of five. The sensitivity to ACLA was independent of the sensitivity to ADR and varied only within a factor of two. Only ACLA showed pronounced increased potency with continuous incubation, and ACLA was the most potent drug in the three cell lines least sensitive to ADR. Two resistant cell lines were selected by treating NCI-H69 in vitro with DAU. One cell line (9-fold resistant to DAU) expressed large amounts of P-glycoprotein, the other cell line (4-fold resistant to DAU) had barely detectable glycoprotein. Both lines acquired resistance to ADR, ACLA and MITO. The cross-resistance to ACLA and MITO was only partial and ACLA was still the most potent drug on these lines. The sensitivity to ACLA of the cell lines least sensitive to ADR suggest that ACLA partially circumvents mechanisms of multidrug resistance. Together with the pronounced increase in potency with prolonged exposure, these results suggest that ACLA has a mechanism of action different from the 'classical' anthracyclines. In this context mitoxantrone is more similar to the classical anthracyclines although its structure is more dissimilar.

Topics: Aclarubicin; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blood Proteins; Carcinoma, Small Cell; Daunorubicin; Doxorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Humans; In Vitro Techniques; Lung Neoplasms; Membrane Glycoproteins; Mitoxantrone; Tumor Stem Cell Assay

Topics: Aclarubicin; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bronchoalveolar Lavage Fluid; Bronchopneumonia; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cisplatin; Cyclophosphamide; Doxorubicin; Humans; Lung; Lung Neoplasms; Male; Methotrexate; Middle Aged; Peplomycin; Vincristine

Topics: Aclarubicin; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Disseminated Intravascular Coagulation; Humans; Lung; Lung Neoplasms; Male; Necrosis; Radiography; Respiratory Distress Syndrome

Marked antimetastatic activity of aclarubicin, an anthracycline antibiotic, was demonstrated on models of spontaneous and artificial metastases of murine tumors such as Lewis lung carcinoma and melanoma B16. The activity depended on the antibiotic dose and administration regimen. The highest antitumor effect of aclarubicin was observed when the antibiotic was used at the earliest periods after intravenous injection of the tumor cells (the model of artificial metastases) or after amputation of the limb with the tumor (spontaneous metastases). Aclarubicin was active after administration by any of the routes used: intravenous, intraperitoneal and oral, the latter by its efficiency being not inferior to the parenteral administration. When used intravenously aclarubicin showed activity similar to that of adriamycin. However, after oral administration only aclarubicin had antimetastatic action.

Topics: Aclarubicin; Administration, Oral; Animals; Drug Evaluation, Preclinical; Injections, Intraperitoneal; Injections, Intravenous; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Time Factors

Topics: Aclarubicin; Aged; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Humans; Lung Neoplasms; Middle Aged; Naphthacenes

Aclacinomycin A (ACLA-A) was administered to 22 patients with metastatic measurable bronchogenic squamous-cell carcinoma in a Phase II trial of the drug. Sixteen patients were fully assessable for response and toxicity. The initial dose of ACLA-A was 85 mg/m2 weekly for 4 consecutive weeks; however, due to severe myelosuppression, the weekly dose was reduced to 65 mg/m2. Fifteen patients were previously untreated. Toxicity was primarily hematological. Complete or partial responses were not observed on this treatment schedule. ACLA-A administered on this schedule lacks therapeutic efficacy in the treatment of patients with advanced bronchogenic squamous-cell carcinoma.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Carcinoma, Bronchogenic; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Evaluation; Humans; Infusions, Intravenous; Lung Neoplasms; Middle Aged; Naphthacenes; Time Factors

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; DNA Polymerase II; Leukemia L1210; Lung Neoplasms; Mice; Naphthacenes; Neoplasms, Experimental

Topics: Aclarubicin; Adult; Aged; Carcinoma, Bronchogenic; Female; Heart; Humans; Infusions, Parenteral; Lung Neoplasms; Male; Middle Aged; Naphthacenes

It would be helpful for successful chemotherapy in cancer patients if a drug-sensitivity test in vitro could predict the exact response of an individual patient's tumor. We have investigated a drug-sensitivity test using human tumor clonogenic assay since 1980. In this paper, results obtained in lung cancer patients are discussed. Specimens for testing were obtained from primary tumor, metastatic mass, malignant pleural and pericardial effusion, and affected bone marrow. Drugs tested in this study were adriamycin, aclarubicin , THP-adriamycin, mitoxantrone, mitomycin C, cis-platinum, 40497 S (an active compound derived from ifosfamide), and methotrexate. Out of 88 specimens tested, 41 (47%) successfully yielded more than 30 colonies per control dish, and were able to evaluate drug-sensitivity. Of those, 32 instances were valid for examination in an in vitro-in vivo association. As a result, 3 were in vitro sensitive-in vivo sensitive, 2 were in vitro sensitive-in vivo resistant, and 27 were in vitro resistant-in vivo resistant. Accordingly, the true positive rate was 60%, and the true negative rate was 100%. In summary, the human tumor clonogenic assay appeared to be an excellent method for testing drug-sensitivity for an individual patient with lung cancer.

Topics: Aclarubicin; Antineoplastic Agents; Cell Count; Cell Division; Cells, Cultured; Cisplatin; Colony-Forming Units Assay; Doxorubicin; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; Mitomycin; Mitomycins; Naphthacenes; Tumor Stem Cell Assay

Intrapleural treatment with aclacinomycin combined with closed tube thoracostomy was used in 7 patients with malignant pleural effusion. Five patients had no recurrence of effusion 3 months after the treatment. Aclacinomycin levels were much higher in blood cells than in plasma, and metabolites were present as the active form. We posit that the local instillation of aclacinomycin is indicated in the management of malignant pleural effusion.

Topics: Aclarubicin; Adenocarcinoma; Adult; Aged; Drainage; Female; Humans; Intubation; Lung Neoplasms; Male; Middle Aged; Naphthacenes; Pleural Effusion; Thorax

A series of experiments with ACM was performed to evaluate the effect for local treatment of malignant pleurisy from the view points of (1) clinical response, (2) pharmacokinetics following intrapleural administration, and (3) pleural reaction. The results were as follows: (1) In 6 patients with malignant pleural effusion, ACM was intrapleurally administered at a dose of 40 mg. In 4 out of the 5 evaluable cases, an extreme decrease in the pleural fluid volume and suppression of reswelling were observed, including 2 cases found to be negative for tumor cells upon cytodiagnosis. (2) In 5 patients, the pharmacokinetics was studied by using compartment model. The clearance curves of ACM in pleural fluid were described by a two-compartment model. The mean half lives of initial phase and terminal phase were 0.78 hr, and 15.28 hr, respectively. The time to reach the maximal whole blood level was 1 to 2 hrs after pleural administration, followed by a slow decline. (3) The pleural reaction to ACM was studied in rabbits by scanning and transmission electron microscope. At a dose of 4 mg per kg of body weight, the shortened microvilli, the degenerated mesothelial cells and the disappearance of basement membrane were observed. On the basis of these findings, we suggest that ACM might be an agent of choice in the treatment of malignant pleurisy.

Topics: Aclarubicin; Adenocarcinoma; Aged; Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Naphthacenes; Pleural Effusion; Rabbits

Aclacinomycin A (ACM) is a new anthracycline antibiotic with a reduced cardiac toxicity in animal models. A phase II study was performed in a total of 25 patients, 23 of whom are evaluable for response. All suffered from recurrent and advanced tumors. Pretreatment consisted of at least four different chemotherapeutic agents (range: 4-9). Lung cancer patients (3/9) were irradiated to the mediastinum. Eighteen patients were pretreated with doxo- or daunomycin. The dose for solid tumors was 2-3 mg/kg given on 3 consecutive days every 3 weeks. Leukemia patients received a daily dose of 20 mg/m2, and standard response criteria were used. Marked reductions of leukocyte counts were achieved in leukemia patients. The overall response rate was about 15% in solid tumors, but major objective responses (CR + PR) have not been observed. Myelosuppression was commonly moderate in solid tumor patients, nausea and vomiting were rare, and alopecia was not induced. Cumulative cardiotoxicity was not evaluated in this trial. Treatment with ACM requires further investigation in acute leukemias and solid tumors, not pretreated with anthracycline antibiotics.

Topics: Aclarubicin; Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Drug Evaluation; Female; Humans; Leukemia; Leukopenia; Lung Neoplasms; Male; Middle Aged; Naphthacenes; Nausea; Thrombocytopenia

Aclacinomycin, isolated from the culture of a Streptomyces, and 4'-O-tetrahydropyranyladriamycin, prepared by chemical derivation, exhibit significantly low cardiac toxicity and more effectiveness than does adriamycin. Pepleomycin, a new derivative of bleomycin, has 4-5 times lower pulmonary toxicity and more potent activity than the parent antibiotic. The future prospects of studies on antibiotics with potential usefulness in treatment of lung cancer are discussed.

Topics: Aclarubicin; Adjuvants, Immunologic; Animals; Antibiotics, Antineoplastic; Bleomycin; Daunorubicin; Doxorubicin; Humans; Leukemia L1210; Lung; Lung Neoplasms; Mice; Molecular Weight; Naphthacenes; Peplomycin; Structure-Activity Relationship

Aclacinomycin A (ACM) is an anthracycline antibiotic recently introduced into clinical trials because of its reduced cardiac toxicity in animal models relative to Adriamycin and daunomycin. This Phase I study of ACM was conducted to determine a dose suitable for i.v. administration on an every-3-week schedule. Twenty-five adult patients with solid tumors were treated with doses of ACM ranging from 60 to 120 mg/sq m i.v. every 3 to 4 weeks. Myelosuppression was the dose-limiting toxicity, but the degree and timing of blood count depression were variable at each dose level. Nausea and vomiting were seen at myelosuppressive doses, but mucositis was rare. Alopecia was seen in approximately one-third of the patients. There was no acute cardiac toxicity, but cumulative cardiac injury could not be evaluated in this trial. There were no major objective responses in three patients who had measurable disease. The recommended doses of ACM for Phase II studies are 100 mg/sq for good-risk patients and 80 mg/sq m for patients who are heavily pretreated or who have a poor performance status.

Topics: Aclarubicin; Adult; Aged; Alopecia; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Female; Hematopoiesis; Humans; Injections, Intravenous; Lung Neoplasms; Male; Middle Aged; Naphthacenes; Nausea; Uterine Cervical Neoplasms

For the purpose of seeking a possible base for the oral clinical application of an anthracycline antibiotic, aclacinomycin A (ACM), ACM was given orally to the mice bearing Lewis lung carcinoma, colon adenocarcinomas 26 and 38, and compared with the effect of adriamycin (ADM). Oral administration of ACM at 5 or 10 mg/kg for 10 time suppressed the growth of Lewis lung carcinoma. There was no significant difference in survival times of the tumor-bearing mice given ACM orally at various dosages tested. ADM was not effective orally as long as the antitumor effect was examined at the dose levels tested. However, significant increase in the survival time of the mice implanted s.c. with colon adenocarcinoma 26 or 38 was noted for oral administration of ACM at 5-10 mg/kg for 10 times. Ths is, at 10 mg/kg of ACM, T/C% was 187% against colon 26 and 141% against colon 38, respectively. ADM, was not effective against these mouse tumors when given orally. Clinical application of ACM by oral administration, however, will need further studied including preclinical pharmacology, drug formulation and others.

Topics: Aclarubicin; Administration, Oral; Animals; Antibiotics, Antineoplastic; Doxorubicin; Lung Neoplasms; Mice; Naphthacenes; Neoplasm Transplantation; Neoplasms, Experimental