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Biomedical subjects

Z Goldberg

Publications and source records attributed to Z Goldberg.

7 recordsLinked to original sources
PubMed2001

An investigation of the molecular basis for the synergistic interaction of tirapazamine and cisplatin.

PURPOSE: To determine if the observed tirapazamine (TPZ)-cisplatin synergistic cell kill was mediated at the cellular level by impairment of upregulation of key proteins involved in repair of DNA interstrand crosslinks. Cisplatin sensitivity has been shown to be dependent on the expression of the two DNA repair proteins ERCC1 and XPA. ERCC1 expression has also been shown to be upregulated by cisplatin exposure. Therefore, these studies were undertaken to determine if hypoxia-activated TPZ pretreatment inhibited the cells' normal protective response to cisplatin via inhibiting the upregulation of ERCC1 and/or XPA expression. METHODS AND MATERIALS: Two different cell lines, one cisplatin sensitive and one cisplatin resistant, were treated with TPZ, cisplatin, both drugs together (which results in additive cytotoxicity), or TPZ followed by cisplatin (which results in synergistic cytotoxicity). All cells were exposed to 1 h of hypoxia to bioactivate the TPZ. Expression of ERCC1 and XPA were evaluated at the mRNA and protein level at 24 or 48 h after drug exposure. RESULTS: In the cisplatin-sensitive non-small-cell lung cancer cell line, ERCC1 expression at the mRNA or protein level was not significantly altered in any of the treatment groups. In the cisplatin-resistant ovarian cancer cell line, ERCC1 expression was upregulated by TPZ, but not by cisplatin alone. The change in protein expression was less pronounced than the change in mRNA level. XPA expression was not significantly changed from baseline in either cell line at the mRNA or protein level. CONCLUSION: In contrast to reports in the literature, this study did not demonstrate cisplatin inducing its own repair by upregulating the DNA crosslink repair proteins ERCC1 or XPA. Therefore, the TPZ-cisplatin synergism cannot be mediated through hypoxia-activated TPZ inhibiting this cellular protective response. TPZ alone, however, was able to alter repair protein expression, which may play a role in mediating its cytotoxicity.

Antineoplastic Agents↗
PubMed2001

c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination.

The p53 protein is subject to Mdm2-mediated degradation by the ubiquitin-proteasome pathway. This degradation requires interaction between p53 and Mdm2 and the subsequent ubiquitination and nuclear export of p53. Exposure of cells to DNA damage results in the stabilization of the p53 protein in the nucleus. However, the underlying mechanism of this effect is poorly defined. Here we demonstrate a key role for c-Abl in the nuclear accumulation of endogenous p53 in cells exposed to DNA damage. This effect of c-Abl is achieved by preventing the ubiquitination and nuclear export of p53 by Mdm2, or by human papillomavirus E6. c-Abl null cells fail to accumulate p53 efficiently following DNA damage. Reconstitution of these cells with physiological levels of c-Abl is sufficient to promote the normal response of p53 to DNA damage via nuclear retention. Our results help to explain how p53 is accumulated in the nucleus in response to DNA damage.

Active Transport, Cell Nucleus↗
PubMed2001

Neoadjuvant therapy for non-small cell lung cancer.

Clinical trials evaluating neoadjuvant or preoperative therapy for locally advanced non-small cell lung cancer (NSCLC) have demonstrated the feasibility, tolerability and activity of this approach. Three randomized trials have reported improved survival in patients with stage III NSCLC treated with preoperative chemotherapy followed by surgical resection compared to surgery alone. Combinations of neoadjuvant chemotherapy plus thoracic radiotherapy have also been investigated, generally resulting in higher rates of pathologic response, but higher toxicity rates as well. The best approach to neoadjuvant therapy remains to be determined and may well be substage dependent. In bulky stage III NSCLC, the role of surgery itself remains unclear and is the subject of an ongoing intergroup trial in the US. Regardless, neoadjuvant therapy has emerged as an important paradigm for clinical research since it serves as an in vivo test of chemosensitivity in patients, and represents a 'window of opportunity' for testing new chemotherapeutic agents and novel strategies. Among the new chemotherapeutic agents being investigated in this setting is docetaxel, one of the most active agents in first- and second-line chemotherapy of NSCLC, and a potent radiosensitizer. Preliminary studies have confirmed the feasibility of integrating docetaxel into neoadjuvant treatment strategies and encouraging results have been reported.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Integration of new chemotherapeutic agents into chemoradiotherapy for stage III non--small cell lung cancer: focus on docetaxel.

Randomized clinical trials have shown that combinations of chemotherapy plus thoracic radiation improve survival compared with radiotherapy alone in stage III non--small cell lung cancer (NSCLC). Furthermore, two recent studies have concluded that concurrent chemoradiotherapy produces superior results to sequential administration. Dependent on the dose and schedule used, chemotherapy may contribute by eradicating distant micrometastases by improving local control as a radiosensitizer, or through both mechanisms. In general, sequential approaches in which full-dose platinum-based chemotherapy precedes thoracic radiation or surgery have improved outcome by impacting distant metastases. In contrast, concurrent chemoradiotherapy using low-dose cisplatin is reported to improve survival by reducing local recurrence without an impact on distant failure rates. In view of these observations, chemoradiotherapy strategies integrating both radiosensitizing agents and dose levels of chemotherapy effective against micrometastases may prove to be most efficacious. Because distant metastases remain the major site of failure, it also is likely that more effective chemotherapy will be required to further improve the current level of response and survival. Fortunately, several newly available chemotherapeutic agents are both highly active against NSCLC and are potent radiosensitizers. In this report we review recent data regarding integration of new chemotherapeutic agents into chemoradiotherapy programs in stage III NSCLC, focusing on trials investigating docetaxel. Encouraging results, including those of the Southwest Oncology Group trial 9504, suggest that docetaxel will play a major role in the future of combined-modality therapy for locally advanced NSCLC. Semin Oncol 28 (suppl 9):26-32.

Carcinoma, Non-Small-Cell Lung↗
PubMed1997

DT-diaphorase: possible roles in cancer chemotherapy and carcinogenesis.

DT-diaphorase [also called NAD(P)H:menadione oxidoreductase; NAD(P)H:(quinone acceptor) oxidoreductase; quinone reductase, azo-dye reductase] (EC.1.6.99.2) has been shown to have a role in activation of quinone-containing cancer chemotherapeutic prodrugs to their active form, as well as inactivation of a variety of xenobiotics involved in carcinogenesis. To illustrate the basis of this dichotomy, a brief review of the historical and recent background of studies on DT-diaphorase is given. Recent data from the laboratory of the authors on the nature of the protein coded for by a recently identified human polymorphism, a C to T transition at nucleotide 609 of DT-diaphorase cDNA, and the frequency of this mutation in anal canal carcinoma patients is presented. Finally, a series of questions about the role of DT-diaphorase in both normal and malignant cells is raised based on the results of others that have been published in the last 2-3 years.

Amino Acid Sequence↗