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Biomedical subjects

M L Friedlander

Publications and source records attributed to M L Friedlander.

At least 19 recordsLinked to original sources
PubMed1996

MDR1 and multidrug resistance-associated protein (MRP) gene expression in epithelial ovarian tumors.

Clinical drug resistance poses a major problem in the successful treatment of ovarian cancer. Two genes, MDR1 and MRP, have been found to play a role in the multidrug resistance phenotype of a number of human tumors. Using a sensitive semiquantitative PCR assay we examined 53 primary untreated ovarian tumors for expression of both MDR1 and MRP genes. Approximately one-third of the tumors expressed MDR1 while all the tumors expressed varying levels of the MRP gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Treatment principles in advanced colorectal cancer.

BACKGROUND: Colorectal cancer is an important disease in the Australian community. Whilst there has been much discussion about the appropriate management of local disease, particularly with respect to the issue of adjuvant therapy, there has been relatively little local discussion of treatment options in metastatic colorectal cancer. METHODS: The critical principles underlying treatment in this setting are briefly outlined in the present article, indicating wherever possible what options could be considered standard, and based on the available literature, which approaches must still be considered experimental at this time. RESULTS: Overall, the results of treatment in this group of patients remain poor. CONCLUSION: Further clinical trials are required to address the issues affecting patients with metastatic colorectal cancer.

Colorectal Neoplasms↗
PubMed1995

Increased expression of the NME1 gene is associated with metastasis in epithelial ovarian cancer.

The genetic events involved in the development of metastases of epithelial ovarian cancer are largely unknown. One gene postulated to play a role in tumour metastasis suppression is NME1 (nm23-H1), and an inverse relationship between NME1 expression and metastatic potential has been observed for some solid tumours. In this study we have investigated the levels of mRNA expression of the 2 isoforms of the NME gene, NME1 and NME2. A maximum of 45 tumours samples from 33 patients were available for Northern blot analysis. We observed variable levels expression of NME1 and NME2 mRNA. The average level of NME1, but not NME2, mRNA expression was statistically higher in metastatic biopsies when compared with primary tumour biopsies. To examine the possible tumour suppressor gene role of NME1 in ovarian tumours, 76 patients were investigated by Southern blot analysis to determine the rate of allelic deletion. Allele loss at 5 other chromosome 17 loci (D17S5, TP53, NF1, D17S74, D17S4) was also evaluated for many of these 76 patients. Allele loss was observed in 22/30 (73%) informative patients at the NME1 locus. We also observed high rates of allele loss at the other loci evaluated. No correlations with clinical stage, histological subtype or patient survival were observed in either mRNA or DNA analyses. We have established that tumour progression in ovarian cancer is accompanied by over-expression of the NME1 gene; however, despite high rates of allele loss at the NME1 locus, the concept that NME1 may be a candidate tumour suppressor gene in ovarian cancer cannot be confirmed by this study.

Base Sequence↗
PubMed1995

Uterine papillary serous carcinoma. A clinical study.

BACKGROUND: Uterine papillary serous carcinoma (UPSC) is a histologic subtype of endometrial adenocarcinoma that is characterized by its papillary architecture, poor differentiation, and advanced stage at initial presentation. It behaves more aggressively than the more common endometrioid adenocarcinoma of the endometrium. METHODS: The history, treatment and follow-up of 18 women with UPSC were evaluated. RESULTS: All women underwent total hysterectomy and bilateral salpingoophorectomy. Positive lymph nodes were found in 6 of 14 patients who underwent pelvic lymphadenectomy. Twelve of 18 women with UPSC had FIGO Stage III and IV tumors in contrast to 30 of 236 patients with endometrioid adenocarcinoma (P < 000.1). Subsequent treatment of these women was: radiotherapy, three women; chemotherapy, four, both radiotherapy and chemotherapy, eight. Chemotherapy consisted of cisplatin/carboplatin plus cyclophosphamide. None of the patients with Stage I or II UPSC died of tumor during a mean follow-up of 31.6 months (range, 12-68 months). Of the women with Stage III and IV disease, 4 of 12 are alive with no evidence of disease after a mean follow-up of 22.5 months (range, 8-45 months). Eight of 12 women who received chemotherapy are alive with no evidence of disease, 4 of whom had Stage III or IV disease. One of six women who did not receive chemotherapy is alive, three died of tumor, and two of intercurrent disease. CONCLUSION: These results would justify further study of the possible role of platinum-based chemotherapy in patients with uterine papillary serous carcinoma.

Aged↗
PubMed1994

Cisplatin-based chemotherapy for ovarian germ cell malignancies: the Australian experience.

PURPOSE: This study was performed to evaluate the Australian experience with cisplatin-based treatment of ovarian germ cell tumors (OGCT) with respect to survival and toxicity of treatment. PATIENTS AND METHODS: A retrospective review was undertaken based on a standardized questionnaire, which was sent to all major gynecologic oncology centers in Australia. RESULTS: Data on 58 patients were obtained. Overall survival at 5 years for all patients was 87%. There was one death from disease among 14 patients with dysgerminoma, and four deaths from disease among 44 patients with nondysgerminomas. Cisplatin-based chemotherapy was associated with a low incidence of serious complications, with only one treatment-related death (from bleomycin-induced respiratory failure). CONCLUSION: Our large series demonstrates that cisplatin-based chemotherapy is highly effective for patients with OGCT. Although direct comparisons cannot be made, the survival of our patients with advanced tumors was comparable to that seen in male germ cell tumors, rather than inferior as is commonly believed. Future studies should aim to refine treatment to minimize toxicity, while further increasing curability.

Adolescent↗
PubMed1992

Prognostic factors in ovarian cancer.

Epithelial ovarian cancers vary considerably in their biologic behavior and this is reflected in the variety of clinicopathologic factors that are used for predicting outcome. This article assesses the potential value of some of the newer prognostic factors and critically evaluates the more commonly used clinicopathologic variables.

Female↗
PubMed1990

Demonstration of somatic rearrangements and genomic heterogeneity in human ovarian cancer by DNA fingerprinting.

A detailed study was performed in 14 patients with epithelial ovarian tumours using the satellite probes 33.15, 228S and 216S to investigate the nature of somatic changes and frequency with which clonal changes could be demonstrated during metastasis and progression. Somatic changes were evident in approximately 70% of ovarian tumours, the most common being a deletion or reduction in intensity of a band suggesting loss of heterozygosity. Additional changes that were observed included increased intensification of single bands and the appearance of novel DNA fragments. Somatic alterations were seen following digestion of DNA with methylation resistant restriction endonucleases indicating that methylation differences alone could not account for all of the somatic changes. Using DNA fingerprint analysis ovarian tumours were shown to be heterogeneous with different DNA patterns observed in different sites in five of eight patients. Generally, within an individual patient the primary and metastases appeared to share a DNA fingerprint pattern with minor variations occurring in different sites suggesting that different populations have derived from a common stem line. This study clearly demonstrates that DNA fingerprint analysis is a sensitive method to detect somatic changes in tumour DNA and for investigating the development of clonal heterogeneity in ovarian tumours.

Adenocarcinoma↗
PubMed1989

Amplification of c-ras-Ki oncogene in human ovarian tumours.

Amplification of the c-ras-Ki oncogene has been the most consistent finding reported in studies on oncogene activation in ovarian cancer, but for the most part the studies have been small and the results conflicting. In order to determine whether amplification occurred de novo in primary tumours or was associated with tumour progression and metastasis, 81 tumour samples from different sites in 26 patients with ovarian tumours and 7 xenografted ovarian tumour cell lines were assayed. Amplification of c-ras-Ki occurred infrequently and was apparent in a single metastatic site in a patient with poorly differentiated serous cystadenocarcinoma of the ovary. Ten-fold amplification of the c-ras-Ki oncogene was also evident in a benign ovarian fibroma. Amplification of the c-ras-Ki oncogene is rare in ovarian tumours and does not appear to play a fundamental role in tumor development or progression.

Blotting, Southern↗
PubMed1989

A phase I study of trimetrexate (NSC 352122) administered by 5-day continuous intravenous infusion.

Trimetrexate (TMTX) is a potent inhibitor of dihydrofolate reductase that circumvents the transport resistance seen with methotrexate and has a wide spectrum of preclinical activity. A total of 18 patients with advanced cancer were treated in a clinical and pharmacological phase I trial with TMTX given as a continuous 5-day intravenous infusion. Neutropenia, thrombocytopenia and stomatitis were the dose-limiting toxicities at the maximum tolerated dose of 50 mg/m2 per 120 h (10 mg/m2 per day for 5 days). There was one septic death associated with neutropenia. Other toxicities were mild rash, mild nausea and transiently raised serum transminase levels. Significant relationships between the dose given and the AUC of plasma TMTX and the steady-state plasma level were established. Significant, although weak, relationships between the percentage of change in neutrophils and platelets and both the AUC and steady-state plasma level of TMTX were also observed. No objective tumour responses were seen, although six patients had stable disease. The recommended phase II dose for a continuous infusion of trimetrexate is 40 mg/m2 per 120 h.

Adult↗
PubMed1989

The relationship of steroid receptor expression to nuclear DNA distribution and clinicopathological characteristics in epithelial ovarian tumors.

Tumor specimens from 92 patients with ovarian carcinoma were analyzed for estrogen receptor (ER), progesterone receptor (PR), proliferative fraction, and ploidy. Seventy-one percent of tumors were either ER+ (greater than 5 fmole/mg protein) or PR+ (greater than 10 fmole/mg protein) with 27% of tumors overall being both ER+ and PR+. There was no significant relationship between receptor expression and stage, grade, or histological subtype. Thirteen percent of diploid tumors were receptor negative in contrast to 38% of aneuploid tumors (P less than 0.01). There was no significant association between ER status and ploidy, but 60% of diploid tumors were PR+ in contrast to 33% of aneuploid tumors (P less than 0.02). Eleven percent of tumors overall were both ER rich and PR rich and comprised 23% of diploid and 5% of aneuploid tumors (P less than 0.01). Receptor-negative tumors had a median S phase of 18.8% which was significantly higher than the median S phase of 12% in receptor-positive tumors (P less than 0.02). A similar analysis was also performed on specimens from 9 patients with borderline epithelial ovarian tumors and 12 with benign epithelial ovarian tumors. Up to 50% of benign and borderline epithelial tumors had measurable receptors, but all were diploid with a relatively low S phase fraction. The functional significance of steroid receptor expression in ovarian cancer is unclear, but the association with ploidy and proliferative activity particularly in patients with malignant ovarian tumors may allow better identification of prognostic subsets and aid in selection of patients for hormonal therapy.

Adult↗
PubMed1989

Comparison of western blot analysis and immunocytochemical detection of P-glycoprotein in multidrug resistant cells.

A sensitive immunocytochemical technique was developed to detect a 170,000 dalton cell membrane glycoprotein (P-gp) in cell lines resistant to vincristine and vinblastine with varying degrees of resistance. P-gp was shown very clearly using the C219 monoclonal antibody and immunocytochemical detection with either antialkaline phosphate or peroxidase-antiperoxidase with silver gold intensification. There was good correlation between the results obtained with immunocytochemical detection of P-gp in single cells and Western blot analysis. The technique is easily performed and can detect P-gp in relatively small numbers of cells that Western blot analysis could miss and is suitable for clinical application.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Alpha-monoamides of methotrexate as potential prodrugs.

alpha-Monoamides of methotrexate were evaluated for their potential as prodrugs. Studies on 11 alpha-monoamides and 5 gamma-monoamides of methotrexate showed that the gamma-monoamides were about as strong inhibitors of Lactobacillus casei dihydrofolate reductase as methotrexate, while I50 of the alpha-monoamides were 1-2 orders higher. The concentration for growth inhibition of murine L1210 cells for methotrexate gamma-propylamide and alpha-propylamide were respectively 1-2 and 2-3 orders higher than that of methotrexate. In contrast, only alpha-monoamides caused significant increase in life span of mice with transplanted L1210 leukaemia, the highest effect being given by the alpha-propyl and the alpha-butylamide. The possibility that the in vivo activity of the alpha-monoamides might be related to in vivo transformation to methotrexate was studied by HPLC analysis of mice serum after administration of the alpha- and gamma-propylamides.

Animals↗
PubMed1988

Ovarian carcinoma: abdominopelvic irradiation following reexploration.

Twenty patients with ovarian cancer, who following reexploration were left with residual disease nodules of less than 2 cm diameter, received abdominopelvic irradiation. Of these patients 18 had previous chemotherapy. Fifteen patients completed treatment, 13 of whom had prior chemotherapy. Six of the 18 patients with invasive tumors were alive and disease free 18-53 months postradiotherapy, while only 4 patients had died at the time of follow-up. No patient with residual nodules greater than 1 cm remained disease free. There was no difference in outcome between patients with microscopic or macroscopic less than 1 cm residuum. Complications were acceptable with 3/20 (15%) developing treatment-related intestinal obstruction.

Adenocarcinoma↗