Leadership Diversity and Development in the Nation's Cancer Centers.

The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute-designated and 18 emerging centers.

A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia.

Purpose: A novel regimen designed to maximize antileukemia activity of carboplatin through inhibiting repair of platinum-DNA adducts was conducted in poor prognosis, acute leukemia patients.

Experimental Design: Patients received fludarabine (10 to 15 mg/m(2) x 5 days), carboplatin (area under the curve 10 to 12 by continuous infusion over 5 days), followed by escalated doses of topotecan infused over 72 hours (fludarabine, carboplatin, topotecan regimen). Twenty-eight patients had acute myelogenous leukemia (7 untreated secondary acute myelogenous leukemia, 11 in first relapse, and 10 in second relapse or refractory), 1 patient had refractory/relapsed acute lymphoblastic leukemia, and 2 patients had untreated chronic myelogenous leukemia blast crisis.

Down-regulation of topoisomerase II alpha is caused by up-regulation of GRP78.

Glucose-regulated protein of M(r) 78kDa (GRP78) is a resident protein of endoplasmic reticulum (ER). We have previously shown that the cells become resistant to topoisomerase II alpha (topo II alpha) targeted cancer chemotherapeutic drug such as etoposide (VP-16) when GRP78 is up-regulated by various means. Up-regulation of GRP78 in V79 Chinese hamster cell lines was achieved by treating the cells with NAD antagonist 6-aminonicotinamide (6AN), inhibitor of glucose metabolism such as 2-deoxyglucose (2dG).

A phase I and pharmacodynamic study of sequential topotecan and etoposide in patients with relapsed or refractory acute myelogenous and lymphoblastic leukemia.

We designed a pharmacokinetic and pharmacodynamic phase I study of sequential topotecan (2.55-6.3mg/m2) by 72h infusion followed by five daily doses of etoposide for patients with refractory acute leukemia based upon synergistic anti-tumor activity of topoisomerase I and II inhibitors in vitro.

Interference with topoisomerase IIalpha potentiates melphalan cytotoxicity.

We studied the consequences of interfering with DNA topoisomerase IIalpha (topo IIalpha) activity on melphalan-induced cytotoxicity. In order to accomplish our goal we used three different approaches to interfere with topo IIalpha. These include: i) use of three V79 Chinese hamster lung fibroblast-derived mutant cell lines, V507, V511, and V513 that are dysfunctional in topo IIalpha activity; ii) treatment of cells with etoposide (VP-16) which inhibits topo IIalpha through the formation of DNA-enzyme cleavable complex; and iii) exposure of cells to merbarone or ICRF-187 (Zinecard) that inhibits the activity of topo IIalpha by restricting its access to DNA.

Green tea constituent (--)-epigallocatechin-3-gallate inhibits topoisomerase I activity in human colon carcinoma cells.

DNA topoisomerases I and II are essential for cell survival and play critical roles in DNA metabolism and structure. Inhibitors of topoisomerase constitute a novel family of antitumor agents with demonstrated clinical activity in human malignancies. The clinical use of these agents is limited due to severe toxic effects on normal cells.

Phase II and pharmacokinetic/pharmacodynamic trial of sequential topoisomerase I and II inhibition with topotecan and etoposide in advanced non-small-cell lung cancer.

Purpose: In vitro and in vivo preclinical models have demonstrated synergistic activity when topoisomerase I and II inhibitors are administered sequentially. Topoisomerase I inhibitors increase topoisomerase II levels and increase cell kill induced by topoisomerase II poisons. We evaluated this hypothesis in a cohort of patients with advanced non-small-cell lung cancer (NSCLC).

Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients.

Purpose: We conducted a phase I and pharmacologic study of a weekly 96-hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites.

Patients And Methods: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed.

Results: In 11 patients who were treated with irinotecan at 12.

Increased sensitivity of human colon cancer cells to DNA cross-linking agents after GRP78 up-regulation.

We have shown earlier that pre-treatment of V79 Chinese hamster cells with 6-aminonicotinamide (6-AN) or 2-deoxyglucose (2-dG) results in over-expression of the Mr 78,000 glucose-regulated stress protein (GRP78) and the subsequent development of resistance to inhibitors of topoisomerase II. These phenomena also occur in V79-derived cell lines that are deficient in poly(ADP-ribose) (p(ADPR)) metabolism. In contrast, over-expression of GRP78 under the conditions outlined above is found to be associated with hypersensitivity to several clinically-relevant DNA cross-linking agents, namely, 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, and melphalan.

Sensitive enzymatic cycling assay for glutathione: measurements of glutathione content and its modulation by buthionine sulfoximine in vivo and in vitro in human colon cancer.

We have measured glutathione content in small tissue samples derived from biopsies of primary and metastatic human colon tumors and from colon cancer cell lines in tissue culture and xenografts in athymic mice. Measurements were performed using an enzymatic cycling assay designed to quantitate extremely low levels of glutathione (GSH) (down to 10(-14) mol) from perchlorate extracts of tissue samples weighing less than 1 mg wet weight. Glutathione was stable in these acid extracts for at least 6 months when stored at -80 degrees C.