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Biomedical subjects

S Holden

Publications and source records attributed to S Holden.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effects of retinoid X receptor-selective ligands on proliferation of prostate cancer cells.

BACKGROUND: Management of prostate cancer that either is detectable by prostate specific antigen (PSA) measurements after curative intent or has spread outside of its capsule is a serious problem. Innovative, nontoxic approaches to the disease are required. One approach might be therapy with retinoids. Retinoid activities are mediated by two distinct families of transcription factors: the retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which can induce transcriptional activation through specific DNA sites or by inhibiting the transcription factor AP-1 that usually mediates cellular proliferative signals. The RARs require heterodimerization with RXRs. RXRs can form either heterodimers or homodimers; and the latter can bind to DNA response elements that are distinct from those bound by the RAR/RXR heterodimers. METHODS: A series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers or RAR/RXR heterodimers, or that selectively inhibit AP-1 activity without activating transcription were evaluated for their ability to inhibit clonal growth of three human prostate cancer cell lines (PC-3, DU-145, and LNCaP). RESULTS: Several notable findings were: 1) RXR-selective retinoids, such as SR11246, were able to inhibit the clonal growth of prostate cancer cells. In contrast, SR11246 had little effect on clonal growth of myeloid leukemic cells. 2) RAR-selective retinoids also inhibited clonal growth of prostate cancer cells. 3) The retinoid (SR11238) with potent anti-AP-1 activity had no effect on the clonal growth of prostate cancer cells. CONCLUSIONS: This study shows that both RXR- and RAR-selective retinoids are worthy of further study and may be candidates for future clinical trials in prostate cancer.

Antineoplastic Agents↗
PubMed1997

Effects of potent vitamin D3 analogs on clonal proliferation of human prostate cancer cell lines.

BACKGROUND: Management of prostate cancer that has spread outside of the prostate capsule is a difficult problem. Innovative, non-toxic approaches to the disease are required. New, relatively non-toxic vitamin D3 analogs have recently been synthesized. We report that several of these compounds have marked antiproliferative effects on prostate cells. METHODS: The clonal antiproliferative activity of five novel analogs of 1,25 dihydroxyvitamin D3 [1,25(OH)2D3, (cmpd C)] as well as 1,25(OH)2D3 itself was tested on three human prostate cancer cell lines (PC-3, LNCaP, and DU-145). The analogs were 20-epi-22oxa-24a,26a,27a-tri-homo-1 alpha,25(OH)2D3 (code name: KH 1060); 24a26a27a-tri-homo-22,24-diene-1 alpha,25(OH)2D3 (code name: EB 1089); 1,25(OH)2-16ene-D3 (code name: HM); 1,25(OH)2-16ene-23yne-D3 (code name: V); 1,25(OH)2-20-epi-D3 (code name: MC 1288)]. RESULTS: With the parent compound [1,25(OH)2D3], the effective dose that inhibited 50% clonogenic growth of PC-3 and LNCaP was 10(-8)M and 7 x 10(-9)M, respectively. For these prostate cancer cell lines, KH 1060 was the most potent analog by an order of 25- to 35-fold as compared to cmpd C. The second and third most potent analogs were HM and MC 1288. DU-145 was resistant to all the vitamin D3 analogs. The major side-effect of 1,25(OH)2D3 is the production of hypercalcemia. The relative inhibitory index (RII) was determined by comparing the antiproliferative activity of the analog to its ability to produce hypercalcemia in mice injected intraperitoneally every other day. The KH 1060 had the best RTI: 50- to 70-fold greater than 1,25(OH)2D3 for PC-3 and LNCaP, respectively. CONCLUSIONS: A trial of one or more of these innovative compounds should be considered for treatment of minimal residual disease of prostate cancer.

Animals↗
PubMed1997

Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin.

We have synthesized and studied the ability of a series of seven novel 1 alpha,25(OH)2 vitamin D3 analogues to inhibit clonal growth of prostate cancer cells (LNCaP, PC-3 and DU-145). Addition of double and triple bonds to the C/D ring (C-16) and side chain (C-22 and C-23) as well as lengthening of the side chain were important for enhanced activity against LNCaP and PC-3. Reorientation of the side chain in the 20-epi configuration resulted in analogues that were extremely potent only against LNCaP (ED50 approximately 5 x 10(-11) M). Compounds with six fluorines on the end of the side chain were very active against both PC-3 and LNCaP (ED50 approximately 2 x 10(-8) M). DU-145 cells were relatively resistant to compounds with all of these modifications, but removal of C-19 (e.g. 1,25(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3) resulted in an analogue that was inhibitory against all three prostate cell lines. Further analysis showed that pulse exposure (3 days, 10(-7) M) to this analogue was enough to inhibit clonal growth of PC-3 cells by 50%. The same exposure also induced cell cycle arrest of all three cell lines, accompanied by upregulated protein expression of the cyclin-dependent kinase inhibitor (CDKI) known as p21waf1 in all three cell lines, and the CDKI known as p27kip1 in LNCaP cells. Associated with upregulation of these CDKIs, partial differentiation occurred as measured by increased expression of both prostate-specific antigen by LNCaP cells and E-cadherin, a cell adhesion protein that may act as a putative tumour suppressor (LNCaP and PC-3 cells). In summary, this is the first report of a potent series of 19-nor-vitamin D3 analogues with the ability to inhibit proliferation of LNCaP, PC-3 and DU-145 prostate cancer cell lines. These compounds may mediate their potent anti-proliferative activities through a cell cycle arrest pathway.

Antineoplastic Agents↗
PubMed1995

High-dose ifosfamide, carboplatin, and etoposide pharmacokinetics: correlation of plasma drug levels with renal toxicity.

An autologous bone marrow transplant regimen of ifosfamide, carboplatin, and etoposide (ICE) has been developed as treatment for certain malignancies. At maximum tolerated doses renal insufficiency precludes dose escalation. The objective was to examine whether measurement of plasma drug levels early during treatment would provide warning of renal failure. Nine patients received a 96-h continuous infusion of ifosfamide 16,000 mg/m2, carboplatin 1600 mg/m2, and etoposide 1200 mg/m2. Pharmacokinetics, including drug levels and plasma concentration-time curves, of ifosfamide, ultrafiltrable platinum (uPt) and etoposide were analyzed and correlated with renal function. One of the nine patients developed anuric renal failure requiring hemodialysis. By 17 h from the start of infusion, this patient showed substantially higher drug levels of ifosfamide (200 vs mean 217 microM) and uPt (19 vs mean 10 microM) than those patients with preserved renal function. The 95% confidence intervals suggested that a 16-22 h ifosfamide level > 153 microM and an uPt level > microM predict the development of significant renal dysfunction. Although drug levels were substantially higher at 56 h, the serum creatinine did not yet reflect kidney injury. This study suggests that high plasma ifosfamide and uPt levels, analyzed early in the course of a 96-h infusion of high-dose ICE, provide warning of severe and potentially fatal renal injury. Since ICE has substantial activity in a number of malignancies, but significant renal morbidity, real-time pharmacokinetic-guided dosing may reduce treatment-related toxicity.

Acute Kidney Injury↗
PubMed1993

beta-cyclodextrin tetradecasulfate/tetrahydrocortisol +/- minocycline as modulators of cancer therapies in vitro and in vivo against primary and metastatic Lewis lung carcinoma.

Tetrahydrocortisol, beta-cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 microM, 24 h) and beta-cyclodextrin tetradecasulfate (100 microM, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 microM, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studied. Tetrahydrocortisol and beta-cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/beta-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14 x 5 mg/kg, days 4-18) and cyclophosphamide (3 x 150 mg/kg, days 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/beta-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.

Animals↗
PubMed1989

Media manipulation of adolescents' personal level judgements regarding consequences of smokeless tobacco use.

Videotapes were developed to try to impact on personal level judgements of concern and risk in the context of smokeless tobacco use, a growing substance use problem in adolescents. In a within-and-between-subjects design, convincingness (i.e., dramatic portrayal) of the videotaped message (high and low) and perceived probability of consequences portrayed in the message (high and low) were manipulated.

Adolescent↗
PubMed1988

Cyclophosphamide and thiotepa with autologous bone marrow transplantation in patients with solid tumors.

Autologous bone marrow transplantation to avoid dose-limiting myelosuppression may allow significant drug dose escalations and exploitation of the linear-log correlation between chemotherapy and tumor cytotoxicity. In a phase I trial of cyclophosphamide and thiotepa (with subsequent addition of melphalan), 23 patients were entered; there were two deaths due to toxic effects. The maximum tolerated dose was 6 g of cyclophosphamide/m2 and 720 mg of thiotepa/m2. No significant dose of melphalan could be added. Stomatitis was dose limiting. Eleven of 20 patients who were able to be evaluated responded. Plasma thiotepa concentrations correlated more closely with toxicity and response than with drug dose level. Continuous infusion cyclophosphamide and thiotepa is an active core regimen for the further design of high-dose combination chemotherapy regimens.

Adult↗
PubMed1987

Fine-needle aspiration biopsy cytology of the breast. A review of the Groote Schuur Hospital experience.

The results of the first 1,500 cytological diagnoses of fine-needle breast aspirates performed at Groote Schuur Hospital Breast Clinic are compared with the histological diagnoses of Tru-cut and excision biopsies of the same lesions. A cytological diagnosis of malignant disease was made in 358 cases, 349 of which were confirmed histologically. The 10 false-positive and 1 false-negative diagnoses are discussed. The reliability of diagnosis in the first 500 cases is compared with that in the second and third 500 cases. There were no false-positive diagnoses in the last 500 cases, and only 3 in the second 500 cases compared with 7 in the first 500 cases. Similarly, the 1 false-negative diagnosis was made in the first 500 cases. The results confirm the reliability of fine-needle aspiration biopsy cytology as a diagnostic technique. The number of incorrect diagnoses decreases as experience with the technique increases.

Biopsy, Needle↗
PubMed1987

The effect of two alpha 2-adrenoreceptor agonists and an antagonist on gastric emptying and mouth to caecum transit time in humans.

Experiments were performed to investigate the effect of two alpha 2-adrenoreceptor agonists, clonidine and lidamidine, and a specific alpha 2-adrenoreceptor antagonist, idazoxan, on gastric emptying and mouth to caecum transit time (MCTT) of a radiolabelled meal in 27 healthy male subjects. Lidamidine (20 mg p.o.) and clonidine (0.3 mg p.o.), given alone had no significant effect on gastric emptying or MCTT suggesting that the anti-diarrhoeal action of clonidine and lidamidine are unlikely to be explained by a slowing of small intestinal transit. Idazoxan (20 mg p.o.) reversed the effect of clonidine in 10 subjects, who showed a delay in MCTT after taking clonidine, but did not alter MCTT under basal conditions. These results suggest that although the sympathetic nervous system can influence upper gastrointestinal motility by an action on alpha 2-adrenoreceptors, this action does not exert a tonic influence on upper gastrointestinal motility under basal conditions.

Adolescent↗
PubMed1987

Effect of cisapride on the gastrointestinal transit of a solid meal in normal human subjects.

The effect of cisapride, a new gastrointestinal prokinetic agent, on the transit of a standard meal through the stomach, small intestine and colon was studied in 10 normal subjects. Cisapride had no significant effect on gastric emptying but decreased mouth to caecum transit time (p less than 0.01). Stool weight and frequency were not significantly increased but the time for the first appearance of stool markers and the arrival of 20% and 50% of stool markers was decreased after cisapride (p less than 0.05).

Adult↗
PubMed1983

Correlations between EMG jaw muscle activity and facial morphology in complete denture wearers.

In a sample of fifteen partially edentulous subjects assigned for immediate complete denture treatment, a correlation analysis was performed between pre-extraction facial morphology determined from lateral cephalograms, and EMG activity of the anterior temporal and masseter muscles in maximal clench and tapping of teeth. Marked correlations observed between vertical and sagittal jaw relations and mean voltages of the jaw-closing muscles indicated strong biting activity in subjects with a square facial type. No significant associations were observed between biting strength and the age of the subjects. Correlations between facial morphological changes and changes in EMG biting activity after denture insertion and during 1 year of denture wear indicated that the anterior temporal muscles were extremely sensitive to sagittal changes in anterior occlusion. The masseter muscles were less sensitive, but responded in some instances to changes in vertical jaw relationship.

Adult↗
PubMed1983

Psychological stress and the passage of a standard meal through the stomach and small intestine in man.

Gastric emptying half-time and mouth to caecum transit time of a solid meal were measured in eight normal volunteers, once during a period of psychological stress and again during a period of relative calm. No consistent or significant effect on gastric emptying was observed, but mouth to caecum transit times were faster in all subjects and this difference was highly significant (p<0.01).

Adult↗
PubMed1980

Jaw muscle activity in complete denture wearers--a longitudinal electromyographic study.

EMG study of subjects wearing immediate complete upper and lower dentures revealed marked alterations in activity of the jaw closing muscles during the biting actions recorded. This finding suggests that changes in jaw and occlusal relationships due to resorption of residual ridges and settling of the dentures also affects jaw muscle activity. The relations between EMG and morphologic findings will be analyzed further in a separate article.

Adult↗
PubMed1979

The rationale of urinary diversion in cancer patients.

A retrospective review of 218 consecutive nephrostomies done on uremic cancer patients has revealed an alarming incidence of postoperative morbidity and mortality. This review has raised legitimate questions regarding the value of palliative urinary diversion. We present a rationale to assist physicians in the management of this clinical problem.

Adolescent↗
PubMed1978

Functional occlusal forces: an investigation by telemetry.

In normal chewing the forces exerted on the occlusal surface seldom exceeded 10 to 15 pounds, as recorded by an eight-channel force transmitter in a removable fixed partial denture. Ninety-five percent of forces were less than 3.5 pounds for subject A, 2.0 pounds for subject B, and 10.0 pounds for subject C. The chewing frequency and the places of maximal force on the occlusal surface were relatively constant. The electromyographic chewing patterns could be considered normal in all circumstances. There was a remarkable statistically significant day-to-day variation in force values. The forces also changed for different kinds of food. The differences between maximum and minimum force values were highest in voluntary, nonfunctional movements.

Arachis↗