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Biomedical subjects

D J Kerr

Publications and source records attributed to D J Kerr.

208 records · Page 12Linked to original sources
PubMedDate not supplied

The myelotoxicity of carboplatin is influenced by the time of its administration.

Previous studies have demonstrated that there are circadian rhythms in susceptibility to a range of commonly used cytotoxic drugs. In this study we have compared the pharmacokinetics and myelotoxicity of carboplatin administered at 18.00 and 06.00 in random order in patients with advanced ovarian carcinoma. Carboplatin treatment at 06.00 is associated with significantly greater thrombocytopenia than at 18.00 (platelet nadir 95,000 versus 180,000, p less than 0.05). There was no pharmacokinetic difference in the patients' handling of ultrafilterable platinum therefore it is possible that there is an intrinsic rhythm of susceptibility of bone marrow to carboplatin.

Blood Cell Count↗
PubMedDate not supplied

The response of breast cancer cells to steroid and peptide growth factors.

Four breast cancer cell lines covering a wide range of receptor characteristics were examined for their growth responses to oestradiol, insulin, EGF and the anti-oestrogen, tamoxifen. Stimulated cellular growth using both the MTT assay and 3H-thymidine incorporation into DNA, was measured against controls grown in a steroid reduced environment. The ER positive MCF-7 cell line showed clear growth responses to E2, insulin and EGF. This was also demonstrated, although to a lesser extent in the ZR-75-1 line which expresses lower levels of ER. In combination, these factors gave an additive growth response but the addition of EGF to maximal concentrations of insulin and oestradiol produced no further increase in growth. In contrast to these results, the two ER negative cell lines examined, MCF-7 Adr and MDA-MB-231 showed no growth response to exogenously applied steroids and in the case of MCF-7 Adr high concentrations of EGF were able to inhibit the growth of this cell line. They also showed high rates of growth in a steroid depleted environment which tends to suggest these cells are growing autonomously through autocrine growth factor induction.

Breast Neoplasms↗
PubMedDate not supplied

The effect of doxorubicin, daunorubicin and 4'-epidoxorubicin on the exogenous c-myc promoter in mouse erythroleukemia cells.

The recombinant plasmids p324, p330 and p323 carrying the aminoglycoside phosphotransferase (aph) gene and 5' flanking c-myc sequences linked to the reporter gene chloramphenicol acetyl-transferase (cat) were introduced into the mouse erythroleukemia cell line F412B2TK- and stable transfectants resistant to geneticin were obtained. The effects of three anthracycline compounds, doxorubicin, daunorubicin and 4'-epidoxorubicin, were studied using a large range of drug concentrations. It was found that 4'-epidoxorubicin and daunorubicin stimulate cat-gene expression with maximum effect at a concentration of 1 micrograms/ml, while doxorubicin enhances transcription from c-myc promoter at 5 micrograms/ml.

Amino Acid Sequence↗
PubMedDate not supplied

The relationship between cytotoxic drug exposure and tumour cell kill, in vitro and in vivo.

Doxorubicin has been shown to be more effective against MGH-U1 bladder carcinoma cells grown in monolayer than spheroid. In vitro clonogenic cell survival curves have been replotted against the area under the concentration-time curve (AUC) for drug exposure and fitted to a Hill plot to derive the parameters E max (maximum possible cell kill) and C50 (drug exposure resulting in half the maximum cell kill). The plasma AUC following intraperitoneal administration of doxorubicin to nude mice was measured using a sensitive and specific HPLC assay and combined with the in vitro cell survival parameters to predict the clonogenic cell survival in MGH-U1 xenografts. The Hill parameters from the spheroid model are better predictors of xenograft clonogenic cell survival than the monolayer parameters. It is possible to predict clonogenic cell survival in solid tumours on the basis of the pharmacokinetics of cytotoxic drug exposure, using a mathematical model based on clonogenic cell kill in vitro.

Animals↗
PubMedDate not supplied

Oncogene transfection of mink lung cells: effect on growth characteristics in vitro and in vivo.

Three sublines have been derived from the parental line Mv1Lu by transfection with normal and mutated Ha-ras, and myc oncogenes, and subsequent cloning. All the oncogenes have increased the growth rate of the cell in vitro, increased their plating efficiency in monolayer and suspension, and reduced their serum dependence. Growth in vivo as xenografts in nude mice has also been increased. Very few tumours were generated from the parental line and those that did form did so after a prolonged lag period, while the transfected lines produced tumours with 100% efficiency, and a short lag period. In general the effects of ras transfection were more extreme, with the highest growth rates and plating efficiencies in vitro and the shortest lag period and doubling times in vivo. There was no increase in plasminogen activator activity as a result of transfection, and the invasive behaviour of the lines in organotypic culture was broadly similar.

Animals↗
PubMedDate not supplied

Chronobiologic quantification of nocturnal low-dose dopamine effect on circadian rhythms of thyroid-related hormones and prolactin (PRL).

Six clinically-healthy young men provided plasma samples every 30 min for 24 h (from 09:00-09:00 on 2 occasions. TSH, free T3 and free T4 were determined in the 30-min samples, while prolactin was determined in samples 1-3h apart. During the first test span, each man received an infusion of physiologic saline between 21(00)-01(00). Upon re-sampling several weeks later, 3 men received a low dose of dopamine (0.1 microgram/kg/min) and 3 men received a high dose (1.0 microgram) over the same hours (21:00-01:00). The least-squares fit of a 24-h cosine to each data series described a statistically-significant circadian rhythm (p less than 0.01) for each subject on each day of study. While overall group comparisons revealed no significant difference in mesor for any hormone studied, some intra-individual differences in rhythm parameters between saline and dopamine infusion were found. Dopamine Rx produced a statistically-significant increase in amplitude for PRL and T4 and an advance in acrophase for TSH, T3 and T4, but a delay for PRL. Studies measuring hormones of interest for the 24th immediately preceding and the 24th immediately following dopamine infusion at varying circadian stages (rather than only between 21:00-01:00) are warranted and have to be individualized--one of the points of this paper. The other main point is that data reduction to a mean and a standard deviation entails loss of information that can be recovered by chronobiologic methods, here used only as a model, in view of the limitations of the sampling design on hand.

Circadian Rhythm↗
PubMedDate not supplied

Bioassay of transforming growth factor-beta activity in acidic protein extracts from primary breast cancer specimens.

Acidic protein extracts have been made from breast tumour specimens, collected at the time of primary surgery. The extracts were partially purified by gel filtration and then tested for transforming growth factor-beta activity in a reproducible cell 3H-thymidine incorporation assay. Purified TGF-beta causes a reproducible increase in NRK colony formation and inhibits incorporation of 3H-thymidine by mink lung cells. However, some of the breast cancer extracts were stimulatory in the mink lung lung assay implying that a mitogenic factor like epidermal growth factor (EGF) was co-purified. Fourteen out of thirty extracts were scored positive for TGF-beta in the NRK colony forming assay and these tumours presented at an earlier clinical stage and were predominantly well differentiated.

Adult↗
PubMedDate not supplied

Sensitization of colorectal and pancreatic cancer cell lines to the prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) by retroviral transduction and expression of the E. coli nitroreductase gene.

Expression of genes encoding prodrug-activating enzymes can increase the susceptibility of tumor cells to prodrugs, and may ultimately achieve a better therapeutic index than conventional chemotherapy. CB1954 is a weak, monofunctional alkylating agent which can be activated by Escherichia coli nitroreductase to a potent dysfunctional alkylating agent which crosslinks DNA. We have inserted the nitroreductase gene into an LNCX-based retroviral vector, to allow efficient gene transfer and expression in colorectal (LS174T) and pancreatic (SUIT2, BxPC3, and AsPC1) cancer cell lines. A clone of LS174T cells expressing nitroreductase showed > 50-fold increased sensitivity to CB1954, and nitroreductase-expressing clones of pancreatic tumor lines were up to approximately 500-fold (SUIT2) more sensitive than parental cells. Concentrations of CB1954 minimally toxic to nontransduced cells achieved 100% cell death in a 50:50 mix of parental cells with SUIT2 cells expressing nitroreductase; and marked "bystander" cell killing was seen with just 10% of cells expressing nitroreductase. Significant bystander cell killing was dependent on a high cell density. In conjunction with regional delivery of vectors and tumor selectivity of cell entry and/or gene expression, nitroreductase and CB1954 may be an attractive combination for prodrug-activating enzyme gene therapy of colorectal and pancreatic cancer.

Antineoplastic Agents↗