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Biomedical subjects

J R Zalcberg

Publications and source records attributed to J R Zalcberg.

At least 19 recordsLinked to original sources
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↗
PubMed1996

Inheritance of chromosome 7 is associated with a drug-resistant phenotype in somatic cell hybrids.

A major form of drug resistance in tumour cells known as classical multidrug resistance (MDR) is associated with the overexpression of the mdr1 gene product, the membrane protein P-glycoprotein (P-gp), which acts as an energy-dependent drug efflux pump. In this study the inheritance of P-gp expression was examined using hybrids formed after somatic cell fusion between a drug-sensitive human T-cell leukaemia cell line, CEM/CCRF, and a drug-resistant derivative, CEM/A7, which is characterized by a clonal chromosomal duplication dup(7)(q11.23q31.2). Fourteen hybrids, chosen at random, were analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) and by binding studies involving the monoclonal antibody MRK16, which recognises an external P-gp epitope. Only two hybrids were positive for both MRK16 antibody labelling and mdr1 mRNA. Partial karyotypic analysis of all hybrids revealed that only the MRK16-positive hybrids contained the duplication in chromosome 7 seen in the CEM/A7 parental MDR line. Therefore, P-gp overexpression in the MRK16-positive hybrids may be linked to the inheritance of chromosome 7 from CEM/A7 and possibly associated with the chromosome 7 abnormality.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Bilateral orchidectomy and flutamide versus orchidectomy alone in newly diagnosed patients with metastatic carcinoma of the prostate--an Australian multicentre trial.

OBJECTIVES: To investigate the hypothesis that maximal androgen blockade improves the outcome of patients with metastatic prostate cancer. PATIENTS AND METHODS: A total of 222 previously untreated patients with metastatic prostatic cancer were entered into a randomized, double-blind, placebo-controlled trial of bilateral orchidectomy with or without androgen blockade (112 receiving flutamide and 110 a placebo) which commenced in 1985 in four Australian centres. The characteristics of the patients, e.g. age, performance status, the presence of bone pain, duration of disease and the use of prior radiation, were well balanced between the groups. Patients commenced the protocol therapy with flutamide or placebo within the 7 days preceding surgery and continued this medication for a minimum of 2 years, unless there was unequivocal evidence of tumour progression. RESULTS: Apart from a difference in grade 3 or 4 gastrointestinal toxicities between the flutamide and placebo arms (13% and 3%, respectively), serious or life-threatening toxicities were uncommon and equally balanced. The assessment of response in six patients (three in each arm) was inevaluable. The objective response rates were 45% and 56% in the flutamide and placebo arms, respectively. There was no difference in survival between the treatments. CONCLUSIONS: This study was not sufficiently powerful to detect small differences in outcome (although the trend in survival favoured the placebo arm) but nevertheless failed to show any benefit for maximal androgen blockade over orchidectomy in this group of patients.

Aged↗
PubMed1996

The role of 5-fluorouracil dose in the adjuvant therapy of colorectal cancer.

BACKGROUND: In many centres, the use of 5-fluorouracil (5-FU) combined with levamisole has become standard therapy for the treatment of patients with Dukes' C colon cancer. However, the role of levamisole remains unclear. MATERIALS AND METHODS: All of the published adjuvant studies for colorectal cancer in which 5-FU (either as a single agent or in combination with other cytotoxics or levamisole) was compared to a no-treatment control group were ranked according to the total planned dose of 5-FU (assuming a body weight of 70 kg or a body surface area of 1.7 m2) over a three-month time frame. The effect of planned total dose of adjuvant therapy on the reduction of mortality was analysed using indirect comparisons of dose on the log odds ratio of death in a linear regression analysis. RESULTS: Overall, this analysis demonstrated a significant reduction in the odds of death for those receiving 5-FU regimens compared to untreated controls (estimate 0.82, 95% CI 0.74 to 0.91, p < 0.001). This effect was larger in those receiving a larger planned dose; for a total dose of 5-FU in the first three months of greater than 10 grams, 8 to 10 grams, less than 8 grams or oral 5-FU, estimates were 0.71, 0.79, 0.93 and 1.04, respectively (p = 0.02 for trend). Similar results were observed when the planned total dose of 5-FU received over 12 months was analysed. The analysis was then repeated by separating those studies in which 5-FU and levamisole were compared to a no-treatment control. A larger effect was seen in the 5-FU/levamisole trials (odds ratio, 0.64) compared to the other 5-FU regimens (odds ratio 0.86, p = 0.04). However, when adjusted for dose, the effect of levamisole was no longer significant (p = 0.09). CONCLUSION: These data suggest two separate hypotheses. The first is that the benefit associated with the use of 5-FU and levamisole given as adjuvant therapy in Dukes' C colon cancer is directly related to the planned total dose of 5-FU administered. Alternatively, in view of the fact that levamisole was part of the treatment regimens in two of the three studies in which the total planned dose of 5-FU exceeded 10 grams in three months (or 40 grams in 12 months), levamisole may be critical to outcome and the 5-FU total dose or dose intensity less relevant.

Antimetabolites, Antineoplastic↗
PubMed1996

Treatment principles in advanced non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) accounts for more than three quarters of all lung tumours and is the leading cause of deaths due to cancer in Australia. More than half of the patients with NSCLC present with advanced disease. Radiation therapy has been the mainstay of active treatment for these patients. There is increasing evidence supporting the benefit of chemotherapy as an addition to radiation therapy in locally advanced non-metastatic disease. The use of cisplatin-based chemotherapy prior to radiation therapy would appear to be a new standard of care in patients with stage III B NSCLC. In advanced (metastic) disease, palliation of symptoms remains the major goal of current treatment programmes. This can be achieved with the best supportive care, radiotherapy, and, in selected patients, platinum-based chemotherapy. Clinical trials to test new treatments, with survival, quality of life and cost-benefit as endpoints, are essential. The present study discusses the current status of conventional and newer treatment methods in locally advanced and metastatic disease.

Antineoplastic Combined Chemotherapy Protocols↗