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Biomedical subjects

D Raghavan

Publications and source records attributed to D Raghavan.

At least 109 records · Page 6Linked to original sources
PubMed1989

Elastase activities of human bladder cancer cell lines derived from high grade invasive tumours.

Elastase activities in intact human bladder cancer cell lines, established from three patients, were measured using a fluorogenic substrate highly specific for elastase, under conditions of physiological pH and ionic strength. This method allowed separation of cell-associated from secreted enzyme activity. As secreted elastase accounted for only 8% of the total, we concluded that the elastases were present at the cell surface. Inhibition studies using extracts of cell-surface elastases showed them to be serine proteinases which were also inhibited by alpha 1-antitrypsin. Partially purified fractions showing the highest specific activity towards the fluorogenic substrate hydrolysed insoluble elastin thus confirming the presence of elastases. This is the first time that elastase activity has been demonstrated in human bladder cancer cells and may represent a mechanism involved in tumour invasion.

Alanine↗
PubMed1989

Site-specific growth of the prostate xenograft line UCRU-PR-2.

A xenografted small-cell, undifferentiated prostate (SCUCP) cancer line, UCRU-Pr-2, was implanted at different sites within nude mice to examine the effect of local environmental factors on tumor growth and behavior. All tumors that grew were small-cell carcinomas. Fragments implanted within muscle and under the kidney capsule were locally invasive; however, tumors that grew subcutaneously or intraperitoneally showed no invasion. UCRU-Pr-2 did not grow in the spleen or the liver. No induced metastases were observed in the lung after intravenous injection. The sites of implantation did not allow the outgrowth of subpopulations as detected by the parameters used: light and electron microscopy, expression of tumor markers, levels of hormone production, and DNA flow cytometry. Electron microscopy, which showed both glandular and neuroendocrine differentiation within the same cell, does not support a dual-cell origin of SCUCP.

Animals↗
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

Detection of tumor-associated membrane proteins in prostate and bladder carcinomas by means of protein blotting.

Analysis of membrane proteins by Western blotting has revealed both overexpression of proteins of molecular weight 10-200 kD (in particular, of proteins of MW less than 43 kD) and increased glycosylation in a xenografted human small cell undifferentiated prostatic carcinoma, and in two xenografted human bladder tumor cell lines compared with preparations from normal human tissue. Of potential functional significance were: a) a 43 kD protein in the bladder line, UCRU-BL-13, which demonstrated increased synthesis and a marked increase in the degree of glycosylation, and b), a 28 kD ConA-binding protein in prostatic tissue which was absent in normal tissue, present in intermediate quantity in a benign hyperplasia and greatly overexpressed in small cell carcinoma. This study demonstrates the utility of the protein blotting/autoradiography technique for the investigation of tumor membrane proteins.

Autoradiography↗
PubMed1989

Dose intensity and outcome with combination chemotherapy for germ cell carcinoma. Australasian Germ Cell Trial Group.

Two hundred and fifty-three patients with advanced stage germ cell carcinoma received induction chemotherapy with vinblastine, bleomycin and cisplatin, sometimes with subsequent surgical resection of residual masses. Overall, 191 patients (76%) achieved complete remission or no evidence of disease after surgery (CR + NED). With 64 months median follow-up only 24 patients have relapsed (13%) and 68% of all patients treated are long-term survivors and 84% of patients entering CR + NED are alive. Toxicity with this chemotherapy was considerable, including seven deaths from leukopenia and septicaemia and eight deaths from bleomycin lung toxicity. Dose reductions or omissions of the drug from the treatment programme was necessary with cisplatin in 8% of patients, with vinblastine in 37% and with bleomycin in 35% of patients. Analysis of these alterations in dose intensity for each drug revealed that initial treatment response and subsequent survival were not compromised by reductions in intended doses of drug administered for either vinblastine or bleomycin. Too few patients had dose reductions of cisplatin for meaningful analysis. This apparent lack of major dose-response effect for either vinblastine or bleomycin in the present treatment programme for germ cell carcinoma has prompted the initiation of a randomized study to determine whether deletion of bleomycin from treatment for patients with good prognostic pretreatment characteristics improves the therapeutic index of this very successful therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Detection of malignant cells in voided urine from patients with bladder cancer, a novel monoclonal assay.

A simple assay is described for detecting malignant cells in the voided urine from patients with transitional cell carcinoma of the bladder. Agarose-embedded urothelial cells from 24 biopsy-proven cancer patients and 10 controls were stained for surface immunofluorescence with four monoclonal antibodies reactive with human bladder cancer and three monoclonals reactive with blood group A. Reactivity was assessed by fluorescence microscopy. One antibody, BLCA-8 appeared to have particular diagnostic utility. Thus, 24.3 +/- 5.8 percent of outer layer and 27.0 +/- 4.6 percent of inner layer urothelial cells reacted with BLCA-8 in patient samples, compared to 2.9 +/- 1.0 and 0.8 +/- 0.5 percent of similar cells from control urines. BLCA-8 antigen expression was found to be relatively stable even after prolonged exposure to urine. In a comparison with conventional cytology, samples from 4/8 patients were considered positive by standard methods, whereas, 8/8 were BLCA-8 positive. This new technique may thus be a useful adjunct to conventional methods.

Animals↗
PubMed1989

A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract.

One hundred eight patients with recurrent or metastatic transitional cell carcinoma of the urothelial tract were randomized to receive cisplatin (C) 80 mg/m2 on day 1 every 4 weeks, or methotrexate (M) 50 mg/m2 on days 1 and 15 plus C 80 mg/m2 on day 2 every 4 weeks (C + M). Fifty-three eligible patients were randomized to C + M and 55 to C. In the C + M arm, 45% of patients responded (complete response [CR], 9%) and 31% (CR, 9%) in the C arm (P = .18). In the C arm, 20 patients failing or relapsing after C received M. Two patients responded, and four with progressive disease (PD) and one with a previous partial response (PR) showed no change. The median survival was 8.7 months (C + M arm) and 7.2 months (C arm), P = .7. Relapse-free survival was not significantly different, but C + M was associated with a significantly increased time to disease progression (median, 5.0 months, v 2.8 months for C arm). The response of untreated patients (37%) was not different from those with prior treatment (39%). On the C + M arm, 92% of patients and 96% of patients on the C arm received 85% or more of the scheduled C dose. Significantly more grade 3 or 4 hematological toxicity (27% v 2%; P = .01) and mucositis (20% v 0%; P = .0005) occurred in patients on the C + M arm. Although the initial response rates seen on the combination arm look superior, and the time to disease progression is increased, these effects have not translated into a clinically important increase in the duration of survival and were associated with increased toxicity.

Adult↗
PubMed1988

Establishment and characterization of a new human bladder cancer cell line showing features of squamous and glandular differentiation.

Tumour-cell heterogeneity has been studied in a continuous cell line, UCRU-BL-17CL, established from a xenografted human primary bladder carcinoma. The cell line, grown in vitro for more than 30 generations, reflects the pathology of both the xenograft from which it was derived and the original human tumour. It comprises mainly adenocarcinoma cells which secrete mucin in vitro, as well as squamous and transitional carcinoma cells. Features of both adenocarcinomatous and squamous differentiation have been observed within the same cell. The line expresses ABH blood group isoantigens, binds to peanut lectin and reacts with monoclonal antibodies (MAbs) raised against keratin and against normal and malignant epithelial cells. It also reacts with MAbs against ras p21 proteins and the epidermal growth factor receptor (EGFR). It shows high levels of lactic acid dehydrogenase isozyme 5, consistent with a high-grade tumour, forms colonies in methylcellulose and is tumorigenic in nude mice. The karyotype (human) shows many marker chromosomes, consistent with expression of EGF receptors and ras p21 proteins, and an 11:13 translocation. DNA content, as studied by flow cytometry, reveals a shift from tetraploid to near triploid. This line may provide a useful model for studies of the histogenesis of bladder cancer and the relationship between transitional-cell carcinoma and the other histological subtypes of this disease.

Aged↗
PubMed1988

A phase II trial of oral 4'demethoxydaunorubicin (DMDR) in inoperable non small cell lung cancer.

4'Demethoxydaunorubicin, an orally active daunorubicin analogue, was administered to 22 patients with inoperable non small cell lung cancer (NSCLC). Patients were stratified into good and poor risk categories and received doses of 45 mg/m2 and 40 mg/m2 respectively at 28 day intervals. All 22 patients were evaluable for response: No tumour responses occurred. Therapy was well tolerated. Mild gastrointestinal toxicity occurred in 41% of patients. Leucopenia with a wcc less than 3 x 10(9)/L occurred in 33% of patients and thrombocytopenia less than 100 x 10(9)/L in 9%. Severe marrow toxicity was rare and there appeared to be no difference in terms of toxicity between the different dose levels. DMDR appears to have no useful clinical activity in NSCLC.

Administration, Oral↗
PubMed1988

Features of squamous and adenocarcinoma in the same cell in a xenografted human transitional cell carcinoma: evidence of a common histogenesis?

Ultrastructural features of squamous differentiation have been found in adenocarcinomatous cells in a xenografted line (UCRU-BL-17) established in nude mice from a primary human bladder transitional cell carcinoma (grade III, stage T4) with a tetraploid DNA component. The line has been characterized by light and electron microscopy, flow cytometry and immunocytochemistry. The initial xenograft showed predominantly adenocarcinomatous differentiation with mucin secretion, whilst the subsequent passages also contained cells showing squamous differentiation. A xenograft subline established from a cell culture of the initial xenograft shows the emergence of a population of cells with near triploid DNA, which are less differentiated, grow more quickly, show decreased expression of carcinoembryonic antigen, and a change in the distribution of staining with peanut lectin from cell surface to cytoplasm. These lines offer an unusual opportunity to study the histogenetic relationships between the histological subtypes of bladder cancer.

Adenocarcinoma↗
PubMed1988

Stability of lectin binding properties expressed by human bladder carcinoma cell lines passaged in vitro or in nude mice.

Binding of a panel of lectins by sublines of two human bladder carcinoma cell lines, UCRU-BL-17 CL and UCRU-BL-13 CL, assessed flow cytometrically following passage of the cells in vitro and in nude mice, was compared with that of human leukaemic cell lines, K562 and HL60, and found to be different. Marked glycosylation of sublines of both bladder cancer cell lines was found compared with normal human bladder transitional epithelium (assessed cytochemically). Neuraminidase pretreatment increased the binding of some lectins indicating that some galactose and N-acetylgalactosamine residues were sialylated. Lectin binding by UCRU-BL-17 CL sublines was remarkably constant on prolonged passage in vitro even though the lines underwent changes in physical characteristics and ploidy when grown in nude mice. This suggests that glycosylation of the tumour cell surface may represent an intrinsic feature of this bladder tumour.

Animals↗
PubMed1988

Ectopic hormone production by a prostatic small cell carcinoma xenograft line.

The xenograft line, UCRU-PR-2, has been characterized further. Established from a primary human undifferentiated small cell carcinoma of the prostate, it has been maintained as a stable xenograft line in nude mice and is currently in passage 9. The tumor has maintained the features of small cell undifferentiated carcinoma but shows epithelial as well as neuroendocrine characteristics. In this paper, we describe synthesis and secretion of peptide hormones, ACTH, beta-endorphin and somatostatin in vivo and ACTH and beta-endorphin in vitro by the tumor, UCRU-PR-2. This suggests that the gene for proopiomelanocortin is expressed and that processing of the molecule occurs. This line may yield insights into the histogenesis of the subtypes of prostate cancer, and also aid studies of regulation of ectopic hormone production.

Adrenocorticotropic Hormone↗
PubMed1988

Pre-emptive (neo-adjuvant) chemotherapy prior to radical radiotherapy for fit septuagenarians with bladder cancer: age itself is not a contra-indication.

Advanced age has often been cited as a contra-indication to the use of cytotoxic chemotherapy or aggressive combined treatment regimens. Fifteen patients, aged between 70 and 79 years (mean 73.1), have been treated for high grade, invasive bladder cancer using neoadjuvant intravenous cisplatin (80-100 mg/m2) plus radical radiotherapy (60 Gy in 6 weeks). Objective response was achieved in 14 patients. The median survival was 22 months, with 6 patients surviving 3 years or longer. Acute and late side effects were not excessive (no cases of W.H.O. grade IV toxicity), as demonstrated by clinical examination and the use of questionnaires (including linear analogue self-assessment scales) to assess quality of life. This aggressive treatment programme can achieve a high remission rate and prolonged survival in elderly patients with high risk bladder cancer without causing excessive morbidity.

Acute Disease↗
PubMed1988

Surveillance for stage I non-seminomatous germ cell tumours of the testis: the optimal protocol has not yet been defined.

Forty-six patients with clinical stage I testicular non-seminomatous germ cell tumours were followed up according to a protocol of active surveillance between 1979 and 1987. The median follow-up time was 40+ months. Thirteen patients (28%) relapsed, predominantly in retroperitoneum and/or lung. Ten of these relapses (76%) occurred within 8 months of orchiectomy. Relapses occurred in 7/35 T1 tumours and 5/10 T2 to T4 tumours. No correlation was detected between the histological type and relapse rate. Three late relapses were diagnosed at 23, 29 and 36 months. Eleven of the relapsed patients remain in prolonged complete remission after PVB chemotherapy +/- surgery; one patient, who initially refused treatment at the time of relapse, has died. Another relapsed with predominant elements of rhabdomyosarcoma intermingled with malignant teratoma in a bone metastasis. He had a partial response to PVB chemotherapy but subsequently died. Thirty-four patients (74%) did not undergo lymphography (LG) and had a higher relapse rate (11/34) than those who had LG (2/12); this was not a statistically significant difference in this small series. The policy of active surveillance is not yet the "state of the art" and should be under constant scrutiny with respect to safety and practice.

Adult↗