amrubicinol and Small-Cell-Lung-Carcinoma

Tumors are presumed to contain a small population of cancer stem cells (CSCs) that initiate tumor growth and promote tumor spreading. Multidrug resistance in CSCs is thought to allow the tumor to evade conventional therapy. This study focused on expression of CD133 and CD87 because CD133 is a putative marker of CSCs in some cancers including lung, and CD87 is associated with a stem-cell-like property in small-cell lung cancer (SCLC). Six SCLC cell lines were used. The expression levels of CD133 and CD87 were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and flow cytometry. CD133+/- and CD87+/- cells were isolated by flow cytometry. The drug sensitivities were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Non-obese diabetic/severe combined immunodeficiency mice were used for the tumor formation assay. SBC-7 cells showed the highest expression levels of both CD133 and CD87 among the cell lines. CD133-/CD87-, CD133+/CD87-, and CD133-/CD87+ cells were isolated from SBC-7 cells; however, CD133+/CD87+ cells could not be obtained. Both CD133+/CD87- and CD133-/CD87+ subpopulations showed a higher resistance to etoposide and paclitaxel and greater re-populating ability than the CD133-/CD87- subpopulation. CD133+/CD87- cells contained more G0 quiescent cells than CD133-/CD87- cells. By contrast, CD133-/CD87- cells showed the highest tumorigenic potential. In conclusion, both CD133 and CD87 proved to be inadequate markers for CSCs; however, they might be beneficial for predicting resistance to chemotherapy.

Topics: AC133 Antigen; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Animals; Anthracyclines; Antigens, CD; Biomarkers, Tumor; Camptothecin; Cell Cycle; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Etoposide; Glycoproteins; Humans; Irinotecan; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Paclitaxel; Peptides; Receptors, Urokinase Plasminogen Activator; Retinal Dehydrogenase; RNA, Messenger; Small Cell Lung Carcinoma

The pharmacokinetic (PK)-pharmacodynamic (PD) relationship of amrubicin and its active metabolite, amrubicinol, has only been evaluated using trough levels of these agents since the full PK profiles not yet been clarified so far. This study was performed to analyze the full PK profiles of amrubicin and amrubicinol and to evaluate their toxicity-PK relationships in Japanese patients.. Amrubicin (35-40 mg/m(2)) was administered to 21 lung cancer patients on days 1-3 every 3-4 weeks. Fourteen blood samples were obtained per patient over the course of 3 administration days. The plasma concentrations of amrubicin and amrubicinol were quantitated by HPLC, and the relationships between PK parameters of these compounds and hematological toxicities were evaluated.. The overall PK profiles of amrubicin and amrubicinol were well characterized using a 3-compartment model and a 1-compartment model with a first-order metabolic process, respectively. The major toxicities were hematological. The clearance of amrubicinol was significantly correlated with grade 4 neutropenia (P = 0.01). The percentage decreases in the neutrophil count, hemoglobin level and platelet count were well correlated with the amrubicinol AUC.. The pharmacokinetic profiles of amrubicin and amrubicinol were clarified, and the subsequent PK-PD analyses indicate that the clearance of amrubicinol is the major determinant of neutropenia.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Carcinoma, Non-Small-Cell Lung; Female; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Small Cell Lung Carcinoma

Amrubicin is a promising agent in the treatment of lung cancer, but predictive biomarkers have not yet been described. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme known to metabolize amrubicinol, the active metabolite of amrubicin, to an inactive compound. We examined the relationship between NQO1 and amrubicinol cytotoxicity.. Gene and protein expression of NQO1, amrubicinol cytotoxicity, and C609T single-nucleotide polymorphism of NQO1 were evaluated in 29 lung cancer cell lines: 14 small cell lung cancer (SCLC) and 15 non-SCLC (NSCLC). The involvement of NQO1 in amrubicinol cytotoxicity was evaluated by small interfering RNA against NQO1.. A significant inverse relationship between both gene and protein expression of NQO1 and amrubicinol cytotoxicity was found in all cell lines. Treatment with NQO1 small interfering RNA increased amrubicinol cytotoxicity and decreased NQO1 expression in both NSCLC and SCLC cells. Furthermore, cell lines genotyped homozygous for the 609T allele showed significantly lower NQO1 protein expression and higher sensitivity for amrubicinol than those with the other genotypes in both NSCLC and SCLC cells.. NQO1 expression is one of the major determinants for amrubicinol cytotoxicity, and C609T single-nucleotide polymorphism of NQO1 could be a predictive biomarker for response to amrubicin treatment.

Topics: Adenocarcinoma; Anthracyclines; Biomarkers, Tumor; Blotting, Western; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; DNA, Neoplasm; Genotype; Humans; Lung Neoplasms; NAD(P)H Dehydrogenase (Quinone); Polymorphism, Single Nucleotide; Real-Time Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Small Cell Lung Carcinoma; Tumor Cells, Cultured

Amrubicin is a new anticancer drug that has been shown to exert efficacy against small cell lung cancer. The pharmacokinetic parameters of amrubicin have not yet been investigated in hemodialysis patients, although it had been expected that amrubicin might not be cleared by hemodialysis because of its high lipid solubility, high protein binding rate and low urinary excretion rate. We encountered a case of small cell lung cancer on hemodialysis who was treated with amrubicin. We assayed the plasma concentrations of amrubicin and amrubicinol (its active metabolite) and analyzed the pharmacokinetic parameters of the drug in this hemodialysis patient. The results revealed that the pharmacokinetic parameters of the drug in this patient undergoing hemodialysis were similar to those in patients not on hemodialysis. Our results suggest that amrubicin and amrubicinol are cleared by hemodialysis, and that dose adjustment of amrubicin might not be required in hemodialysis patients.

Topics: Anthracyclines; Antineoplastic Agents; Humans; Lung Neoplasms; Male; Middle Aged; Renal Dialysis; Small Cell Lung Carcinoma