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The Oncologist 1999New agents for the palliative treatment of metastatic breast cancer have emerged in the 1990s. This review summarizes the response rates of these agents with an emphasis... (Review)
Review
PURPOSE
New agents for the palliative treatment of metastatic breast cancer have emerged in the 1990s. This review summarizes the response rates of these agents with an emphasis on recent findings, such as presentations from the 1998 Meeting of the American Society of Clinical Oncology.
METHODS
The English medical literature was reviewed to identify clinical trials involving monotherapy for the treatment of metastatic breast cancer. Three agents--paclitaxel, vinorelbine, and docetaxel--are emphasized because their databases are extensive enough to allow interesting comparisons. Liposomal-encapsulated anthracyclines, losoxantrone, gemcitabine, oral surrogates of continuous-infusion fluorouracil, raltitrexed, LY 231514, edatrexate, topoisomerase I inhibitors, and trastuzumab are reviewed briefly.
RESULTS
Many of the new agents produce response rates approaching or even surpassing those achievable with doxorubicin monotherapy. Compared with older agents, some new agents have improved or at least different safety profiles, and some are easier to administer.
DISCUSSION AND CONCLUSIONS
The new agents offer useful therapeutic options that make them suitable for combining with each other and with older agents, which could result in more effective regimens for metastatic disease, and, ultimately, primary disease in the adjuvant setting. The chemotherapeutic paradigms governing the management of breast cancer for the past three decades are likely to change as we move into the 21st century.
Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Docetaxel; Dose-Response Relationship, Drug; Female; Humans; Paclitaxel; Palliative Care; Taxoids; Vinblastine; Vinorelbine
PubMed: 10337368
DOI: No ID Found -
British Journal of Cancer Feb 2002Losoxantrone is a DNA intercalator that was developed with the potential to replace anthracyclines. The recommended single agent dose of losoxantrone is 50 mg m(-2)... (Clinical Trial)
Clinical Trial
Losoxantrone is a DNA intercalator that was developed with the potential to replace anthracyclines. The recommended single agent dose of losoxantrone is 50 mg m(-2) every 3 weeks. We conducted a phase I study of losoxantrone and a fixed dose of cyclophosphamide on a q3 weekly schedule. Forty-nine patients were enrolled, of which 46 were evaluable for toxicity. The dose-limiting toxicity was neutropenia at the maximum tolerable losoxantrone dose of 45 mg m(-2). With granulocyte colony-stimulating factor support, significant further dose escalation of losoxantrone was achieved. Cardiotoxicity was seen with cumulative dosing. Pharmacokinetics of losoxantrone revealed linear kinetics and triphasic clearance, with significant interpatient variability. No objective responses were seen in this study. Neutropenia was dose-limiting in this combination with or without granulocyte colony-stimulating factor support. The recommended dose for further testing is cyclophosphamide 500 mg m(-2) followed by losoxantrone 95 mg m(-2) with granulocyte colony-stimulating factor support.
Topics: Adult; Aged; Anthraquinones; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Neutropenia; Neutrophils; Pyrazoles; Pyrazolones
PubMed: 11870533
DOI: 10.1038/sj.bjc.6600123 -
Scientific Reports Nov 2014Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is...
Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality. In the context of kinase specificities, an extensive library of anthrapyrazolone analogues has been investigated for the selective inhibition of c-JNK and thereby to gain control over the inflammation associated risks. In our comprehensive biochemical characterization, it is observed that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the obtained results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis.
Topics: Animals; Anthraquinones; Endotoxins; Gene Expression; Hydrophobic and Hydrophilic Interactions; Inflammation; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred C57BL; Pyrazolones; Shock, Septic; Signal Transduction; Small Molecule Libraries
PubMed: 25428720
DOI: 10.1038/srep07214 -
Blood Aug 2005Several primary murine and human B lymphomas and cell lines were found to constitutively express high levels of the activated form of c-jun N-terminal kinase (JNK), a...
Several primary murine and human B lymphomas and cell lines were found to constitutively express high levels of the activated form of c-jun N-terminal kinase (JNK), a member of the mitogen-activated protein (MAP) kinase family. Proliferation of murine B lymphomas CH31, CH12.Lx, BKS-2, and WEHI-231 and the human B lymphomas BJAB, RAMOS, RAJI, OCI-Ly7, and OCI-Ly10 was strongly inhibited by SP600125, an anthrapyrazolone inhibitor of JNK, in a dose-dependent manner. The lymphoma cells underwent apoptosis and arrested at the G2/M phase of cell cycle. Furthermore, JNK-specific small interfering RNA (siRNA) inhibited the growth of both murine and human B lymphomas. Thus in the B-lymphoma model, JNK appears to have a unique prosurvival role. Survival signals provided by CD40 and interleukin-10 (IL-10) together reversed the growth inhibition induced by the JNK inhibitor. c-Myc protein levels were reduced in the presence of both SP600125 and JNK-specific siRNA, and CD40 ligation restored c-Myc levels. Moreover, Bcl-xL rescued WEHI-231 cells from apoptosis induced by the JNK inhibitor. The JNK inhibitor also reduced levels of early growth response gene-1 (Egr-1) protein, and overexpressing Egr-1 partially rescued lymphoma cells from apoptosis. Thus, JNK may act via c-Myc and Egr-1, which were shown to be important for B-lymphoma survival and growth.
Topics: Animals; Anthraquinones; Apoptosis; Cell Proliferation; Cell Survival; DNA-Binding Proteins; Early Growth Response Protein 1; G2 Phase; Gene Expression Regulation, Neoplastic; Humans; Immediate-Early Proteins; JNK Mitogen-Activated Protein Kinases; Lymphoma, B-Cell; Mice; Proto-Oncogene Proteins c-myc; Pyrazolones; RNA, Small Interfering; Transcription Factors; Tumor Cells, Cultured
PubMed: 15890690
DOI: 10.1182/blood-2004-10-3819 -
Proceedings of the National Academy of... Nov 2001Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and...
Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 (K(i) = 0.19 microM). SP600125 is a reversible ATP-competitive inhibitor with >20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genes COX-2, IL-2, IFN-gamma, TNF-alpha, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-alpha and inhibited anti-CD3-induced apoptosis of CD4(+) CD8(+) thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
Topics: Adenosine Triphosphate; Animals; Anthracenes; Anthraquinones; Binding, Competitive; CD4-Positive T-Lymphocytes; Cell Differentiation; Cells, Cultured; Cytokines; Enzyme Inhibitors; Female; Gene Expression; Humans; JNK Mitogen-Activated Protein Kinases; Jurkat Cells; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Molecular Structure; Monocytes; Protein Kinase Inhibitors; Pyrazoles; Pyrazolones; Structure-Activity Relationship; Tumor Necrosis Factor-alpha
PubMed: 11717429
DOI: 10.1073/pnas.251194298 -
British Journal of Cancer Dec 1987Two P388 cell lines with acquired resistance to daunorubicin have been shown to exhibit cross-resistance to anthrapyrazolone (NSC 357885). The degree of cross-resistance... (Comparative Study)
Comparative Study
Two P388 cell lines with acquired resistance to daunorubicin have been shown to exhibit cross-resistance to anthrapyrazolone (NSC 357885). The degree of cross-resistance observed in these cell lines (58 and 150 fold) is similar to those observed towards daunorubicin (34 and 142 fold). However the decreased drug accumulation observed for daunorubicin in the resistant cell lines (4-6 fold) is not observed for anthrapyrazolone. Similarly, verapamil can increase daunorubicin accumulation in resistant cells but has no effect on anthrapyrazolone accumulation. It is concluded that in contrast to daunorubicin, decreased anthrapyrazolone accumulation is not the resistance mechanism operative in daunorubicin resistant cell lines towards anthrapyrazolone.
Topics: Animals; Anthraquinones; Antineoplastic Agents; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance; Leukemia P388; Leukemia, Experimental; Mice; Pyrazoles; Pyrazolones; Time Factors; Tumor Cells, Cultured; Verapamil
PubMed: 3435702
DOI: 10.1038/bjc.1987.283