PURPOSE Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds. EXPERIMENTAL DESIGN Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene ...

Thirty patients with cisplatin-refractory germ cell tumor were treated with high-dose carboplatin, etoposide, and cyclophosphamide and autologous bone marrow transplantation. The total dose of carboplatin was 1500 mg/m2, etoposide 1200 mg/m2, and cyclophosphamide was increased by increments from 60 to 150 mg/kg. Twenty-five cycles of treatment, given to 17 patients, did not include granulocyte-...

Much effort has been directed at identifying molecular markers in human tumors that predict response and/or survival after treatment with chemotherapeutic agents. Molecular predictors help to identify patients most likely to benefit from a particular therapy, with the ultimate goal of selecting optimal treatment for each patient. Gene microarray analysis has already identified genes that may be...

Cyclophosphamide is used to treat a wide range of human malignancies. However, it is also a known carcinogen associated with induction of therapy-related leukemia and bladder cancer. The DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), protects cells from the toxic and mutagenic effects of O6-alkylating agents. We report here the contribution of AGT in protecting against the toxi...

High-risk neuroblastoma is an aggressive malignancy, with high rates of treatment failure. We evaluated genetic variants associated with in vitro sensitivity to two derivatives of cyclophosphamide for association with clinical response in a separate replication cohort of neuroblastoma patients (n = 2,709). To determine sensitivity, lymphoblastoid cell lines (LCLs) were exposed to increasing con...

The in vitro cytotoxicity and mechanism of action of cyclophosphamide (CP) were studied in a dual cell culture system, using rat hepatocytes and K562 human chronic myeloid leukemia cells. Cytotoxicity and DNA damage were measurable in K562 cells using CP concentrations that are clinically attainable. Alkaline elution analysis of cellular DNA demonstrated the presence of concentration- and time-...

The respiratory tract epithelium of dogs, from the nose to the lungs, was examined for cytochrome P-450 and associated biotransformation activities. In the ethmoturbinates, where olfactory epithelium is located, the amount of cytochrome P-450 was comparable to that in the liver, when measured on the basis of activity per milligram of microsomal protein. The rest of the nasal region also contain...

In a previous study, we observed that the elimination clearance of 4-hydroxycyclophosphamide (HCY) in patients receiving cyclophosphamide (CY) 60 mg/kg/day by 1-h i.v. infusion for 2 consecutive days decreased from day 1 to day 2 due to an apparent decrease in human aldehyde dehydrogenase 1 (ALDH1) activity. Here, the mechanism for the decrease in ALDH1 activity after CY administration was inve...

A synthetic method for the preparation of 1,8-dihydroindeno[2,1-b]pyrroles and pyrrol-2-yl methanols in an enantioselective manner that relies on chiral gold(I)-catalysed reactions β-amino-1,4-enynols is described. divergence product selectivity was achieved by exploiting electrostatic interactions between counteranion metal catalyst substrate. With a gold(I) complex containing N-triflyl phosph...