PubMed Health⌕ Search

Biomedical subjects

T S Ganesan

Publications and source records attributed to T S Ganesan.

At least 19 recordsLinked to original sources
PubMed1998

Cyclophosphamide, methotrexate and infusional 5-fluorouracil (infusional CMF) in metastatic breast cancer.

Bolus 5-fluorouracil (5-FU) is a phase-specific drug with a short plasma half-life that is used in combination with bolus cyclophosphamide and methotrexate in the treatment of breast cancer. The efficacy of 5-FU can be improved by continuous intravenous infusion using portable infusion pumps (infusional 5-FU). Infusional 5-FU, 200 mg m(-2) day(-1), in combination with standard doses of bolus cyclophosphamide and methotrexate, was evaluated in a phase I/II dose-finding study. The cyclophosphamide and methotrexate were administered in 28-day cycles as follows: cohort 1, cyclophosphamide 600 mg m(-2), days 1 and 8, and methotrexate 40 mg m(-2), day 1; cohort 2, cyclophosphamide 400 mg m(-2), days 1 and 8, and methotrexate 40 mg m(-2), day 1; cohort 3, cyclophosphamide 480 mg (m-2), days 1 and 8, and methotrexate 40 mg m(-2), day 1; cohort 4, cyclophosphamide 480 mg m(-2), days 1 and 8, and methotrexate 40 mg m(-2), days 1 and 8. Median overall survival was 10 months (range 3-21 months). Objective tumour responses were seen in 9 of 25 patients (36%, 95% CI 18-58%), including 3 of 13 patients (23%) previously treated for metastatic disease. Cohorts 1 and 4 proved to be too toxic, with five of six patients in cohort 1 and three of four in cohort 4 developing grade III/IV neutropenia. The dose intensity of cyclophosphamide achieved was as follows: cohort 1, 82%; cohort 2, 86%; cohort 3, 97%; cohort 4, 90%. Infusional 5-FU can be administered safely and is effective in combination with cyclophosphamide 480 mg m(-2), days 1 and 8, and methotrexate 40 mg m(-2), day 1, in the treatment of metastatic breast cancer.

Adult↗
PubMed1998

Phase I study of the mitomycin C analogue BMS-181174.

BMS-181174 is an aminodisulphide derivative of Mitomycin C (MMC) with activity against a range of tumour cell lines and xenografts, including MMC-resistant tumours. In a phase I study of 82 patients with confirmed malignancy, we administered BMS-181174 at doses of 0.8-75 mg m(-2) by intravenous injection every 28 days. At least three patients were evaluated at each dose level, and 174 courses were administered. The pharmacokinetics were dose linear at BMS-181174 doses of 11.5-75 mg m(-2) and the drug appeared to undergo wide distribution. The maximum-tolerated dose was 65 mg m(-2) in previously treated patients and 75 mg m(-2) in chemotherapy-naive cases. The dose-limiting toxicity was myelosuppression, particularly thrombocytopenia, which was prolonged and cumulative. Three patients treated at 65-75 mg m(-2) died suddenly with evidence of pneumonia/pneumonitis, thought to be drug-related. Other toxicities included thrombophlebitis, possible cardiotoxicity (asymptomatic, reversible decline in left ventricular function) and renal impairment. The partial response rate was 5% (4 out of 82) overall, and 9% (3 out of 32) in patients treated at 65-75 mg m(-2). Responses occurred in treated and previously-untreated patients, including cases of colorectal cancer, non-small-cell lung cancer, ovarian cancer and adenocarcinoma of unknown primary site. BMS-181174 has anti-cancer activity but, because of its toxicity, particularly pneumonitis and thrombophlebitis, no phase II studies are planned.

Adult↗
PubMed1997

Immunohistochemical expression of inhibin/activin subunits in epithelial and granulosa cell tumours of the ovary.

Dimeric inhibin-A has been shown recently by a sensitive two-site ELISA assay to be a useful tumour marker in granulosa cell tumours of the ovary. It is also elevated in some patients with malignant epithelial ovarian tumours. To identify the precise subunits of inhibin expressed in ovarian tumours, three monoclonal antibodies, R1, E4, and INPRO (against the alpha C-, beta A-, and pro-alpha-subunits, respectively), were evaluated by immunohistochemistry on a panel of six granulosa cell and nine epithelial tumours. All granulosa cell tumours stained positively with E4 and R1, suggesting expression of dimeric inhibin-A; in two patients where serum levels were measured pre-operatively, they were elevated. The tumours also reacted weakly with INPRO, suggesting the presence of precursor forms of the alpha-subunit. Eight malignant epithelial ovarian tumours expressed the beta A-subunit only, as recognized by E4, while one tumour expressed both alpha- and beta A-subunits, which correlated with an elevated serum inhibin-A level. Thus, while granulosa cell tumours express inhibin, the majority of epithelial tumours probably express activin, a result which needs to be confirmed by serum measurements.

Activins↗
PubMed1997

Analysis of loss of heterozygosity and KRAS2 mutations in ovarian neoplasms: clinicopathological correlations.

The molecular events that give rise to ovarian epithelial neoplasms are not well understood. In particular, it is not known whether adenocarcinomas arise from benign or low malignant potential (LMP) precursors. We have examined a large series of benign (25) and LMP (31) ovarian tumors for loss of heterozygosity (LOH) at multiple loci on 17 chromosomes. LOH was observed in benign tumors on chromosomes 6 (14%) and 9 (5%) and on the X chromosome (33%) only. LOH on these chromosomes was also detected in a small number of LMP neoplasms, suggesting that these may derive sometimes from benign precursors. In addition, we examined LOH in 93 adenocarcinomas. Analysis of associations between LOH events showed that LOH on chromosomes 5 and 17 (P = 0.0002) and on chromosomes 17 and 18 (P = 0.00007) were associated significantly with each other, which suggests that these may represent cooperative, progressive events. No novel significant associations were identified between LOH events and stage, grade, or histology, which would indicate the existence of genetic heterogeneity in ovarian neoplasms. KRAS2 mutations were detected more often in LMP neoplasms than in malignant tumors (P = 0.004) and were detected more often in Stage I/II malignant tumors than in Stage III/IV malignant tumors (P = 0.033), suggesting that LMP tumors with KRAS2 mutations are unlikely to progress to frank malignancy. Univariate (but not multivariate) survival analysis showed that LOH of chromosomes 11 (P = 0.039) and 17 (P = 0.04) was associated with a significantly worse prognosis. Replication of these novel findings is necessary, and the identification, isolation, and characterization of the critical genes affected by LOH will determine their importance in the pathogenesis of ovarian malignancies.

Chromosome Deletion↗
PubMed1997

Molecular approaches to diagnosis and management of ovarian cancer.

The recent advances in the understanding of the pathogenesis of ovarian cancer have been helpful in addressing issues in diagnosis, prognosis and management. The study of ovarian tumours by novel techniques such as immunohistochemistry, fluorescent in situ hybridisation, comparative genomic hybridisation, polymerase chain reaction and new tumour markers have aided the evaluation and application of new concepts into clinical practice. The correlation of novel surrogate tumour specific features with response to treatment and outcome in patients has defined prognostic factors which may allow the future design of tailored therapy based on a molecular profile of the tumour. These have also been used to design new approaches to therapy such as antibody targeting and gene therapy. The delineation of roles of c-erbB2, c-fms and other novel receptor kinases in the pathogenesis of ovarian cancer has led initially to the development of anti-c-erbB2 monoclonal antibody therapy. The discovery of BRCA1 and BRCA2 genes will have an impact in the diagnosis and the prevention of familial ovarian cancer. The important role played by recessive genes such as p53 in cancer has raised the possibility of restoration of gene function by gene therapy. Although the pathological diagnosis of ovarian cancer is still confirmed principally on morphological features, addition of newer investigations will increasingly be useful in addressing difficult diagnostic problems. The increasingly rapid pace of discovery of genes important in disease, makes it imperative that the evaluation of their contribution in the pathogenesis of ovarian cancer is undertaken swiftly, thus improving the overall management of patients and their outcome.

Biomarkers, Tumor↗
PubMed1997

A phase II study of mitomycin C and oral etoposide for advanced adenocarcinoma of the upper gastrointestinal tract.

BACKGROUND: Mitomycin C and etoposide have both demonstrated activity against gastric carcinoma. Etoposide is a topoisomerase II inhibitor with evidence for phase-specific and schedule-dependent activity. PATIENTS AND METHOD: Twenty-eight consecutive patients with advanced upper gastrointestinal adenocarcinoma were treated with intravenous (i.v.) bolus mitomycin C 6 mg/m2 on day 1 every 21 days to a maximum of four courses. Oral etoposide capsules 50 mg b.i.d. (or 35 mg b.i.d. liquid) were administered days 1 to 10 extending to 14 days in subsequent courses if absolute neutrophil count > 1.5 x 10(9)/l on day 14 of first course, for up to six courses. RESULTS: Twenty-six patients were assessed for response of whom 12 had measurable disease and 14 evaluable disease. Four patients had a documented response (one complete remission, three partial remissions) with an objective response rate of 15% (95% confidence interval (95% CI) 4%-35%). Eight patients had stable disease and 14 progressive disease. The median survival was six months. The schedule was well tolerated with no treatment-related deaths. Nine patients experienced leucopenia (seven grade II and two grade III). Nausea and vomiting (eight grade II, one grade III), fatigue (eight grade II, two grade III) and anaemia (seven grade II, two grade III) were the predominant toxicities. CONCLUSION: This out-patient schedule is well tolerated and shows modest activity in the treatment of advanced upper gastrointestinal adenocarcinoma. Further studies using protracted schedules of etoposide both orally and as infusional treatment should be developed.

Adenocarcinoma↗
PubMed1996

Susceptibility to human papillomavirus-associated cervical intra-epithelial neoplasia is determined by specific HLA DR-DQ alleles.

Human papillomaviruses (HPV) play a causative role in the aetiology of cervical intra-epithelial neoplasia (CIN) and cervical cancer. Human leukocyte antigens (HLA) are important in the regulation of immune response to foreign antigens. The role of genetic variation at the HLA class II loci (DR and DQ) in CIN (HPV 16, 18, 31 and 33 typed) was investigated by PCR DNA amplification and oligonucleotide probe typing of cervical smears from British Caucasian patients (n = 176) and controls (n = 416). The alleles of the DQB1*03, DRB1*04 and DRB1*11 loci were strongly associated with susceptibility to CIN. Specifically, the haplotypes DRB1*0401-DQB1*0301 and DRB1*1101-DQB1*0301 were significant and indicated susceptibility. The DQB1*03 locus was more contributory to this association than the DRB1 loci. A weak protective effect was shown for the haplotype DRB1*0101-DQB1*0501. Positive correlation was also observed for HPV-positive CIN, suggesting that specific HLA class II alleles may be important in determining the immune response to HPV antigens and the risk for CIN after HPV infection. Our results should help in the rational design of vaccines against HPV.

Alleles↗
PubMed1996

Allele loss on chromosome arm 6q and fine mapping of the region at 6q27 in epithelial ovarian cancer.

Genetic changes have been shown to be important in determining the multistep progression of cancer. Allele loss studies and karyotypic analysis of epithelial ovarian tumours have indicated the presence of putative tumour suppressor genes on chromosomes 6, 11, 13, 17, 18, 22, and X. We have focused on chromosome arm 6q to identify the minimal region that may contain a putative tumour suppressor gene. Nineteen polymorphic microsatellite markers from 6q and one centromeric marker (D6S294) have been used to detect allele loss in 68 ovarian tumours (six benign, six borderline, and 56 with malignant histology). Allele loss was evaluated by separation of fluorescence labelled polymerase chain reaction-amplified products. Forty-six of fifty-six (82%) malignant tumours showed allele loss on 6q, whereas only four of 56 had lost all the markers tested. Forty-one of fifty-six (73%) malignant tumours showed allele loss at 6q26-27. The minimal region of allele loss was between markers D6S264 and D6S297 (3 cM), with maximal allele loss of 62% at D6S193 and 52% at D6S297. Three tumours showed loss of D6S193 only, while retaining flanking informative markers. Allele loss around 6q26-27 was observed in all histological types of epithelial ovarian cancer and did not correlate with any clinical factors. In addition, there was allele loss at ESR (56%) and D6S286 (47%), though a minimal region was not defined. Allele loss at 6q12-25 correlated significantly with endometrioid and mucinous ovarian malignant tumours (P = 0.01). The physical mapping of the region between D6S297 and D6S264 will allow the eventual identification of the putative tumour suppressor gene.

Adult↗
PubMed1996

The genomic structure of discoidin receptor tyrosine kinase.

The discoidin domain receptor (DDR) is a new class of receptor tyrosine kinase that is distinguished by a unique extracellular domain homologous to the lectin Discoidin I found Dictyostelium discoideum. A cosmid was isolated from a human chromosome 6 cosmid library containing the DDR gene. A complete genomic contig of the DDR gene was constructed from seven subclones of the cosmid. The cosmid fragments were analyzed by PCR, sequencing, and comparison of genomic/cDNA sequence. The DDR gene is composed of 17 exons, ranging in size from 96 to 1014 bp, distributed along approximately 12 kb of genomic DNA. The extracellular domain is encoded by 8 exons of which three code for the discoidin domain. The transmembrane domain is encoded by 1 exon, the juxtamembrane by 3 exons, and the catalytic domain by 5 exons. The generation of the two splice variants of DDR, EDDR1 and EDDR2 are explained by the genomic structure. Exon 11 (111 bp in the juxtamembrane domain) is present in DDR and absent in the splice variant EDDR1. An inverted repeat of 20 bp was identified at the 3' exon-intron junction of exon 11, which results in a lariat loop-like secondary structure. EDDR2 is generated because of a cryptic splice acceptor site that results in an extra 18 bp (6 amino acids) inserted 5' of exon 14 in the catalytic domain. A polymorphic (GT)17 repeat was identified in intron 5 with a heterozygosity of 0.71. The exon-intron structure of the DDR gene will be helpful in further understanding of its function and explains the possible structural basis for the two splice variants.

Alternative Splicing↗
PubMed1996

H-RYK, an unusual receptor kinase: isolation and analysis of expression in ovarian cancer.

BACKGROUND: Protein tyrosine kinases play an important role in cellular metabolism as key components of signal transduction pathways. They are involved in cellular growth, differentiation, and development. Receptor tyrosine kinases (EGF receptor and c-erbB2) have been shown to be important in the pathogenesis of cancer. In ovarian cancer, overexpression of c-erbB2, a type I receptor, has been correlated with an adverse effect on survival of patients. MATERIAL AND METHODS: An unusual receptor tyrosine kinase, H-RYK, has been isolated from a complimentary DNA library of SKOV-3, an epithelial ovarian cancer cell line, using a polymerase chain reaction-mediated approach. RESULTS: The primary structure of the predicted amino acid sequence of the protein shows a novel NH2-terminal region. The catalytic region shows homology to other tyrosine kinases, the closest homology being with v-sea (39%). A significant alteration in the catalytic domain is that the highly conserved "DFG" triplet in subdomain VII is altered to "DNA." The gene was mapped to chromosome 3q22. A single transcript of 3.0 kb is expressed in heart, brain, lung, placenta, liver, muscle, kidney, and pancreas by Northern analysis with maximal expression in skeletal muscle. In situ hybridization analysis on human tissues demonstrated localization of message in the epithelial and stromal compartment of tissues such as brain, lung, colon, kidney, and breast. There was minimal to absent expression of H-RYK on surface epithelium of ovaries. In benign (3) and borderline tumors of the ovary (5), there was expression in the stromal compartment. However, in malignant tumors (24) there was increased expression predominantly confined to the epithelium. Polyclonal antisera raised against synthetic peptides recognize a 100-kD protein in ovarian cancer cells and other cell lines. In contrast to other receptor tyrosine kinases, the receptor did not phosphorylate in an in vitro kinase assay. CONCLUSIONS: The expression of this unusual receptor tyrosine kinase in epithelial ovarian cancer suggests that it may be involved in tumor progression, which needs further investigation.

Adenocarcinoma↗
PubMed1995

Localization of an epithelial-specific receptor kinase (EDDR1) to chromosome 6q16.

A protein receptor tyrosine kinase (EDDR1) has been isolated from a complementary DNA library of SKOV-3, an epithelial ovarian cancer cell line. The primary structure of the predicted amino acid sequence of the protein shows a novel N-terminal region that has homology to a factor VIII-like domain. The C-terminal catalytic domain has all of the canonical sequence motifs of a receptor tyrosine kinase with homology to the TRK-2H protein (49%), which suggests that it is a type II receptor. It is expressed in epithelial cells of several tissues. To determine the chromosomal localization of the gene, somatic cell hybrids were analyzed by PCR amplification using oligonucleotide primers specific for EDDR1. Segregation was observed to a hybrid containing human chromosome 6. Cosmids for EDDR1 were isolated from a human chromosome 6 cosmid library and were shown by fluorescence in situ hybridization to map to 6q16.

Base Sequence↗
PubMed1995

AF6 gene on chromosome band 6q27 maps distal to the minimal region of deletion in epithelial ovarian cancer.

Chromosome 6 has been shown to contain at band q27 a minimal region of deletion associated with epithelial ovarian cancers and AF6, a gene disrupted in acute myeloid leukemia with t(6;11)(q27;q23). Using rapid amplification of cDNA ends by polymerase chain reaction, the breakpoint in AF6 was confirmed and a cDNA clone identified. This clone was used as a probe to screen a chromosome 6 cosmid library, and a single cosmid C-109F0645 was isolated. By fluorescence in situ hybridization, C-109F0465 was found to map distal to the critically deleted region associated with ovarian malignancies. AF6 is therefore distinct from and lies telomeric to this region.

Acute Disease↗
PubMed1995

Inhibin as a marker for ovarian cancer.

Inhibin is a polypeptide hormone produced by the granulosa cells of the ovary, and is present in body fluids as dimers of various sizes each comprising an alpha- and beta-subunit. Free forms of the alpha-subunit also circulate, and the presently available radioimmunoassay (Monash assay) cannot distinguish these from biologically active dimeric inhibin. Recently we described a new two-site enzyme immunoassay able for the first time to measure the levels of dimeric inhibin throughout the human menstrual cycle. The sensitivity limit of this assay is 2 pg ml-1 in human serum with cross-reactivity against activin of 0.05%. The normal range of inhibin in post-menopausal women is < 5 pg ml-1, in pre-menopausal women 2-80 pg ml-1 (2-10 pg ml-1 in the follicular phase, 40-80 pg ml-1 in the luteal phase). This assay was used to determine inhibin levels in sera from 15 (five pre-menopausal and ten post-menopausal) patients with granulosa cell tumours of the ovary. It was raised in a pre-menopausal patient preoperatively (261 pg ml-1), in six post-menopausal patients (32, 43, 54, 66, 24 and 58 pg ml-1) and one pre-menopausal patient with recurrent tumour, (237 pg ml-1), all confirmed clinically. Inhibin was normal in six patients in remission. Oestradiol levels were normal in all patients. Serial levels of inhibin predicted recurrence before overt clinical relapse in two patients. In 29 patients with malignant epithelial ovarian tumours inhibin levels were modestly elevated in nine and normal in the rest. Three patients with endometrioid histology, two with undifferentiated tumours, three with mucinous adenocarcinoma and one with clear cell carcinoma had elevated inhibin levels. Functional inhibin is secreted by all granulosa cell tumours of the ovary studied and can be used as a tumour marker to determine response to therapy and predict recurrence and is superior to oestradiol. A more detailed analysis of the levels of inhibin, and its subunits in epithelial ovarian cancer is needed to identify the molecular forms of the immunoreactive material before optimised assays can be applied to this more common tumour.

Adult↗
PubMed1995

Association between HLA DQB1 * 03 and cervical intra-epithelial neoplasia.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) and cervical cancer have been shown to be strongly associated with infection by human papillomavirus (HPV). However, other factors may be contributory in the progression from normal epithelium to CIN and cervical cancer, since not all women with HPV infection develop disease. Recently, it was demonstrated that there is a high risk for cervical cancer and CIN in women with HLA DQB1 * 03 (RR = 7.1, p < 0.0009) (1). Subsequent reports have been conflicting, due to sample size, genetic heterogeneity and differences in the techniques employed for the detection of HLA DQB1 * 03. MATERIALS AND METHODS: DNA from cervical smears of 178 women with CIN and 420 controls with normal cervical cytology was analyzed by polymerase chain reaction (PCR) with type-specific primers for HPV 16, 18, 31, and 33. The DNA from test and control samples were also analyzed by a novel PCR technique, which mutates the first base of codon 40 (DQ alleles) from T to G to create an artificial restriction site for an enzyme Mlu I that distinguish DQB1 * 03 from other alleles and are confirmed by digestion of amplified DNA with Mlu I. Further analysis of individual DQB1 * 03 alleles was performed using PCR and allele-specific primers. RESULTS: One hundred forty-four (34%) out of 420 controls (all HPV 16, 18, 31, or 33 negative and normal cytology), 37/66 (56%) of CIN I and 72/112 (64%) of CIN III were positive for DQB1 * 03 (trend test, p < 0.001, chi 2 = 37.3). A significant association was observed between DQB1 * 03 and CIN (odds ratio 3.03; 95% CI 2.11-3.45). Of women with CIN, 131/178 (73.5%) had HPV (types 16, 18, 31, or 33) infection. There was a significant association between DQB1 * 03 and presence of HPV (odds ratio 3.43; 95% CI 2.25-5.10). Homozygosity for DQB1 * 03 was more strongly associated with CIN than heterozygosity (odds ratios 4.0 and 2.63, respectively); and for the presence of HPV (odds ratio 4.47; 95% CI 2.58-7.77). HLA DQB1 * 0301 was the most strongly associated allele with CIN and HPV (odds ratios 2.53 and 2.63, respectively). CONCLUSIONS: HLA DQB1 * 03 is associated significantly with CIN and may be permissive for HPV infection. Further analysis of class II HLA typing in CIN is necessary to evaluate this association.

Base Sequence↗