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J R Zalcberg

Publications and source records attributed to J R Zalcberg.

At least 19 recordsLinked to original sources
PubMed1999

Altered multidrug resistance phenotype caused by anthracycline analogues and cytosine arabinoside in myeloid leukemia.

The expression of P-glycoprotein (Pgp) is often increased in acute myeloid leukemia (AML). However, little is known of the regulation of Pgp expression by cytotoxics in AML. We examined whether Pgp expression and function in leukemic blasts was altered after a short exposure to cytotoxics. Blasts were isolated from 19 patients with AML (15 patients) or chronic myeloid leukemia in blastic transformation (BT-CML, 4 patients). Pgp expression and function were analyzed by flow cytometric analysis of MRK 16 binding and Rhodamine 123 retention, respectively. At equitoxic concentrations, ex vivo exposure for 16 hours to the anthracyclines epirubicin (EPI), daunomycin (DAU), idarubicin (IDA), or MX2 or the nucleoside analogue cytosine arabinoside (AraC) differentially upregulated MDR1/Pgp expression in Pgp-negative and Pgp-positive blast cells. In Pgp-negative blasts, all four anthracyclines and AraC significantly increased Pgp expression (P =.01) and Pgp function (P =.03). In contrast, MX2, DAU, and AraC were the most potent in inducing Pgp expression and function in Pgp positive blasts (P <.05). A good correlation between increased Pgp expression and function was observed in Pgp-negative (r =.90, P =.0001) and Pgp-positive blasts (r =.77, P =.0002). This increase in Pgp expression and function was inhibited by the addition of 1 micromol/L PSC 833 to blast cells at the time of their exposure to these cytotoxics. In 1 patient with AML, an increase in Pgp levels was observed in vivo at 4 and 16 hours after the administration of standard chemotherapy with DAU/AraC. Upregulation of Pgp expression was also demonstrated ex vivo in blasts harvested from this patient before the commencement of treatment. In 3 other cases (1 patient with AML and 2 with BT-CML) in which blasts were Pgp negative at the time of initial clinical presentation, serial samples at 1 to 5 months after chemotherapy showed the presence of Pgp-positive blasts. All 3 patients had refractory disease. Interestingly, in all 3 cases, upregulation of Pgp by cytotoxics was demonstrated ex vivo in blasts harvested at the time of presentation. These data suggest that upregulation of the MDR1 gene may represent a normal response of leukemic cells to cytotoxic stress and may contribute to clinical drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Colorectal cancer.

Explore the source record for details and available documents.

Antineoplastic Agents↗
PubMed1999

Physical mapping of a tandem duplication on the long arm of chromosome 7 associated with a multidrug resistant phenotype.

Both the expression of the multidrug transporter, P-glycoprotein (Pgp), and abnormalities of the long arm of chromosome 7 have been shown to be adverse prognostic indicators in acute leukemias. In this study, a clonal duplication, dup(7)(q11.1q31.1), inherited with the classical multidrug resistant phenotype in a drug-resistant derivative of a human T-cell leukemia cell line was characterized. The position of the duplication was of interest as the gene which encodes Pgp, MDR1, is located on the long arm of chromosome 7 at position 7q21.1. Fluorescence in situ hybridization (FISH) analysis with a chromosome 7-specific painting probe confirmed the composition of the abnormal chromosome. A YAC clone hybridizing to the MDR1 locus confirmed that this gene was located within the duplicated region of the derivative chromosome. With a panel of well-characterized YAC clones, the duplicated segment was found to be a direct tandem duplication, somewhat larger than estimated by conventional cytogenetics. The proximal and distal breakpoints of the abnormality were located and a YAC clone spanning the distal breakpoint was identified. This clone is of particular interest, as it harbors the markers D7S523 and D7S471, close to which a putative tumor suppressor gene is thought to lie. Further examination of the breakpoint region may therefore illuminate the mechanism of Pgp upregulation as well as providing information about a tumor suppressor gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Induction of insulin-like growth factor binding protein expression by ICI 182,780 in a tamoxifen-resistant human breast cancer cell line.

Earlier studies in our laboratory demonstrated that the steroidal antiestrogen ICI 182,780 is very effective in abolishing the tamoxifen-resistant proliferation of MCF 7/5-23 cells. In addition, preliminary binding studies showed that ICI 182,780 increased the binding of insulin-like growth factor (IGF)-I to the MCF 7/5-23 cells, although this finding was not the result of an increase in the expression of the insulin-like growth factor-I receptor (IGF-IR). Hence, we reasoned that the inhibition of tamoxifen-resistant cell growth by ICI 182,780 might have been due to increased expression of insulin-like growth factor binding proteins (IGFBPs). We observed the up-regulation of non-insulin-suppressible IGF-I binding in both the tamoxifen-sensitive MCF 7/5-21 cell line (1.5-fold) and the tamoxifen-resistant MCF 7/5-23 cell line (2.5-fold) after 5 days of treatment with ICI 182,780 (10(-7) M) in serum-free medium, suggesting a role for cell-associated IGFBPs. Affinity cross-linking experiments confirmed the presence of an IGF-I:IGFBP complex of approximately 38-kDa in tamoxifen or ICI 182,780-treated cells. Western ligand blots showed higher levels of a soluble 30-kDa IGFBP in media conditioned by either of the subclones that had been treated with ICI 182,780, an effect consistently opposed by estrogen (E2: 10(-9) M). RT-PCR showed higher levels of IGFBP-5 mRNA than any of the other known IGFBPs, suggesting that this was the major IGFBP subtype. The protein was subsequently identified by Western immunoblotting as IGFBP-5. In conclusion, we postulate that this may be a mechanism contributing to the greater potency of ICI 182,780 in the growth inhibition of the MCF 7/5-23, tamoxifen-resistant cell line.

Antineoplastic Agents↗
PubMed1999

Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line.

The relationship between oestrogen (E2) and insulin-like growth factor-one (IGF-1) was examined in both tamoxifen-sensitive (MCF 7/5-21) and tamoxifen-resistant (MCF 7/5-23) subclones of the MCF 7 cell line. Both subclones were grown in defined, serum-free (SF) medium over a period of 7 days with the addition of E2 or IGF-1 or a combination of both agents. Growth of both MCF 7/5-21 and 7/5-23 cells was stimulated (245% and 350%, respectively) by E2. However, only the growth of MCF 7/5-23 cells was stimulated (266%) by IGF-1. A combination of E2 and IGF-1 significantly enhanced MCF 7/5-21 and 7/5-23 cell growth (581% and 695%, respectively). E2-induced IGF-1 receptor (IGF-1R) levels (as measured by 125I-IGF-1 binding and Northern analyses) in only MCF 7/5-23 cells. This effect was partially inhibited by tamoxifen. In medium containing serum, the growth of only the MCF 7/5-23 cells was significantly inhibited by the IGF-1R monoclonal antibody, alphaIR-3. The detection of E2-induced expression of IGF-2 using RT-PCR was demonstrated in the MCF 7/5-23 cells. These experiments indicate that E2 may sensitize tamoxifen-resistant MCF 7/5-23 cells to the growth stimulatory actions of IGF-2 via up-regulation of the IGF-1R and describes a cell-survival mechanism that may manifest itself as tamoxifen resistance.

Breast Neoplasms↗
PubMed1999

Overview of docetaxel (Taxotere)/cisplatin combination in non-small cell lung cancer.

Cisplatin-based chemotherapy is effective in non-small cell lung cancer (NSCLC), although it prolongs survival only modestly. Single-agent docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is highly active against NSCLC. The activity and tolerability of two docetaxel/ cisplatin regimens were therefore investigated in two multicenter phase II studies, one in Australia and one in France. Chemotherapy-naive patients with inoperable NSCLC received either docetaxel 75 mg/m2 on day 1 plus cisplatin 75 mg/m2 3 weekly (n = 47; Australian study) or docetaxel 75 mg/m2 on day 1 plus cisplatin 100 mg/m2 every 3 weeks for three cycles then every 6 weeks (n = 51; French study). The majority of the population (74%) had metastatic disease. Seventy-eight patients were evaluable for efficacy. Overall response rates were 36% (95% confidence interval, 25 to 47) in all evaluable patients and 34% in patients with metastases. Median duration of response was 6 months, with a 4-month median time to progression. Median survival time was 9 months, with a 1-year survival rate of 34%. A median of four (range, one to nine) treatment cycles were administered. Febrile neutropenia occurred in 14% of patients. Severe infection, which occurred in less than 7% of patients, led to two toxic deaths. Other severe toxicities were rare, with severe stomatitis and severe neurosensory side effects reported in 2% and 1%, respectively, of treated patients. No severe fluid retention occurred. Docetaxel/cisplatin, administered as two different schedules, is well tolerated and exhibits efficacy in the range of the most established combinations in the treatment of advanced NSCLC.

Adult↗
PubMed1998

Update on adjuvant treatment of colorectal cancer.

Developments in the adjuvant therapy of colorectal cancer have been reported recently. Important questions regarding the most appropriate regimen, the optimal duration of treatment, the preferred route of administration, and which subgroups are most likely to benefit are addressed. A number of studies in rectal cancer considered the timing of chemoradiation, mode of administration of chemotherapy, and the role of intraoperative radiotherapy. Quality of life issues also are being addressed. Several new agents and novel therapies have produced interesting and, it is hoped, clinically useful results. The prognostic significance of a number of molecular markers also is the subject of ongoing research.

Chemotherapy, Adjuvant↗
PubMed1998

5-fluorouracil: a pharmacological paradigm in the use of cytotoxics.

1. Painstaking progress in drug development is well illustrated by 5-fluorouracil (5FU), originally designed 40 years ago as a fluorinated analogue of the naturally occurring base uracil. Innovative pharmacokinetic and pharmacodynamic strategies have seen significant clinical improvements for cancer patients over the past decade. 2. 5-Fluorouracil acts by three main mechanisms. Principally, the intermediate metabolite fluorodeoxyuridine monophosphate inhibits a key enzyme in pyrimidine biosynthesis, namely thymidylate synthase (TS). Additionally, 5FU is metabolized to ribo- and deoxy-ribonucleotides, which act as false bases for incorporation into RNA and DNA. 3. Biomodulation of 5FU has been attempted with methotrexate (MTX), folinic acid, interferons, cisplatin and radiotherapy. Methotrexate augments the actions of 5FU by inhibiting dihydrofolate reductase and decreasing the folate pool required for pyrimidine biosynthesis, inhibiting TS via MTX-polyglutamate and directly inhibiting purine biosynthesis. Interferons increase steady state concentrations of 5FU. 5-Fluorouracil enhances the cytotoxicity of cisplatin and radiotherapy by inhibiting DNA repair. Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex. 4. 5-Fluorouracil has a short plasma half-life. Thymidylate synthase inhibition is limited to the S-phase of the cell cycle and only a small fraction of most cancer cells are in S-phase at any one time. Increased response rates seen with infusional protocols may reflect the effective recruitment of additional mechanisms of cytotoxicity, not dependent on cell cycle, including effects on RNA synthesis. 5. Patients with localized metastatic disease may benefit from locoregional treatments. These include hepatic intra-arterial therapy with related compounds, such as floxuridine, which reach high concentrations at sites of tumour, while systemic toxicities are minimized by efficient hepatic clearance. 6. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil. Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodulation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.

Antimetabolites, Antineoplastic↗
PubMed1997

Australian multicentre phase II trial of paclitaxel in women with metastatic breast cancer and prior chemotherapy.

OBJECTIVE: To determine the efficacy and safety of paclitaxel given as a three-hour infusion in patients with metastatic breast cancer which had progressed despite hormonal therapy and/or chemotherapy. DESIGN AND SETTING: Multicentre phase it trial undertaken in five major centres or hospitals in Sydney, Melbourne and Adelaide. PATIENTS AND METHODS: 50 patients with clinically or radiologically measurable or evaluable metastatic breast cancer recruited between March and July 1993. All had received prior chemotherapy, with subsequent disease progression. INTERVENTION: Paclitaxel (Anzatax, Faulding) was given at a dose of 175 mg/m2 intravenously over three hours every three weeks for up to nine courses. MAIN OUTCOME MEASURES: Response rate (partial or complete); duration of progression-free survival; duration of survival; and adverse reactions. RESULTS: Patients had a median age of 51 years; 62% had received at least two prior drug regimens for metastatic breast cancer and 48% had anthracycline-resistant tumours. A median of six paclitaxel courses was given per patient. Overall response rate was 18% (95% confidence interval [95% CI], 9%-31%), with complete responses in four patients (8%). In patients with anthracycline-resistant tumours, response rate was 25% (95% CI, 10%-47%). Response was not influenced by extent of prior treatment. Estimated median progression-free survival was 4.1 months (95% CI, 3.2-6.0 months) and estimated median survival was 6.3 months (95% CI, 6.2-10.3 months). Treatment was well tolerated, with neutropenia the major toxic effect. CONCLUSIONS: Paclitaxel (three-hour infusion) has significant activity in heavily pretreated patients with metastatic breast cancer, including anthracycline-resistant tumours.

Adult↗
PubMed1997

Clinical issues in euthanasia.

We consider the euthanasia debate from the perspective of the clinical interface between doctors, patients and their families-a perspective that is lacking in much public discussion of euthanasia (defined as the deliberate taking of an individual's life at their request).

Attitude to Death↗
PubMed1997

Expression of mdr1 and mrp in the normal B-cell homologue of B-cell chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukaemia (CLL) cells commonly express the multidrug resistance phenotype. The aim of this study was to establish whether the normal homologue in B-cell ontogeny of B-CLL also expressed the multidrug resistance (mdr) phenotype. Human tonsillar lymphocytes were sorted to yield two B-cell subsets based on the expression of CD19, CD5 and CD10. The normal homologue was represented by a population of B cells that was CD19 positive, CD10 negative and weakly expressed CD5. Based upon functional analysis and the detection of mdr1 mRNA by semi-quantitative PCR, these cells expressed the mdr phenotype. In contrast, functional multidrug resistance could not be demonstrated in CD19-positive CD10-positive cells with strong expression of CD5, nor could mdr1 mRNA be found in these cells. MRP was variably expressed in both B-cell subsets with no discernable differences in the pattern of expression. We conclude that normal B cells with a phenotype resembling that of B-CLL cells express the multidrug resistance phenotype.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1997

Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance.

One of the most important forms of drug resistance in acute myeloid leukemia is the multidrug resistance (MDR) phenotype, which is characterized by the expression of the MDR1 gene product, P-glycoprotein. Although a number of factors affect MDR1 gene expression, the genetic events that "switch on" the human MDR1 gene in tumor cells that were previously P-glycoprotein negative have remained elusive. Here, we report evidence that the methylation status of the human MDR1 promoter may serve as a basis for this "switch." Based on Southern analysis using methylation-sensitive and methylation-insensitive restriction enzymes, a tight correlation was found between MDR phenotype and demethylation of the 5' region of the MDR1 gene in a human T cell leukemia cell line. Similar results were obtained from the analysis of P-glycoprotein-positive and P-glycoprotein-negative samples of chronic lymphocytic leukemia. Treatment of the cell lines with the demethylating agent 5'-azadeoxycytidine altered the methylation pattern of the MDR1 promoter in P-glycoprotein-negative cells to resemble that of P-glycoprotein-positive cells and activated the promoter such that MDR1 mRNA was now detectable. Treatment also resulted in an increased resistance to epirubicin and decreased daunomycin accumulation, both of which were reversible by verapamil, a characteristic of the classical MDR phenotype in cells expressing P-glycoprotein. These results suggest that the MDR phenotype may be acquired as a result of changes in methylation of the MDR1 promoter.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Modulation of the function of human MDR1 P-glycoprotein by the antimalarial drug mefloquine.

MDR1 P-glycoprotein in membranes of human tumor cells of the CEM/VBL100 line was selectively labelled using photoreactive analogs of verapamil, N-(p-azido-3-[125I]salicyl)amino-verapamil ([125I]ASA-V) and prazosin, 2-[4-(4-azido-3-[125I]iodobenzoyl)piperazin-1-yl]4 -amino-6,7-dimethoxyyquinazoline ([125I]ASA-P). Mefloquine, a quinolinemethanol antimalarial drug, was shown to inhibit the labelling of P-glycoprotein with an efficiency similar to that for verapamil, a known chemosensitizer. By contrast, chloroquine competed poorly for the binding site on P-glycoprotein. Mefloquine also inhibited the functional activity of P-glycoprotein. It decreased the rates of extrusion of [3H]vinblastine and the fluorescent dyes, fluo-3 acetomethoxy ester and rhodamine 123, from drug-resistant cells and decreased the level of resistance of these cells to vinblastine. The ability of mefloquine to inhibit P-glycoprotein function may be involved in the neurotoxic side-effects occasionally associated with the use of mefloquine as an antimalarial drug.

ATP Binding Cassette Transporter, Subfamily B, Mem↗