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Biomedical subjects

A T Cockett

Publications and source records attributed to A T Cockett.

At least 73 records · Page 4Linked to original sources
PubMed1990

Influence of high-energy shock waves and cisplatin on antitumor effect in murine bladder cancer.

The potential application of high-energy shock waves (HESW) for control of experimental bladder cancer was investigated. Subcutaneous 3-d murine bladder cancer (MBT-2) in C3H mice were exposed to HESW alone (250 to 1,500 shocks) or in combination with cisplatin (5 to 10 mg/kg, i.p.). Although HESW alone showed no influence on tumor growth, HESW/cisplatin combination therapy suppressed tumor growth more than cisplatin alone. Subsequent studies revealed that an air-fluid interface relative to tumor location played a pivotal role for the chemosensitizing effect of HESW. HESW treatment was able to enhance the cisplatin cytotoxicity only when the tumors were placed adjacent to the air-fluid interface.

Animals↗
PubMed1989

Differential effects of cyclosporin on hepatic and renal heme, cytochrome P-450 and drug metabolism. Possible role in nephrotoxicity of the drug.

Treatment of rats with 25 or 50 mg/kg cyclosporin A for 6 days elicited vastly different responses in hepatic and renal heme and drug metabolism activities. In the liver, cytochrome P-450 concentration was decreased significantly (to 70-75% of the control). This was accompanied by a marked reduction in benzo[a]pyrene hydroxylase activity (to 20-28% of the control). Aniline hydroxylation was also decreased, but to a lesser extent (to 77% of the control). In contrast, in the kidney cytochrome P-450 concentration was significantly increased to (145-170% of the control), along with a modest decrease in benzo[a]pyrene hydroxylation activity. In this organ, the concentration of porphyrins was severely decreased (to 30% of the control). Also, the activities of delta-aminolevulinate (ALA) synthetase and ALA dehydratase, as well as that of heme oxygenase, were inhibited. It is suggested that in the kidney the inhibition of degradation, rather than an enhanced rate of synthesis of the heme molecule, contributes to the observed increase in cytochrome P-450 concentration. In the liver, the decrease in the cytochrome concentration could not be explained in terms of an alteration in the rate of heme biosynthesis or degradation. Therefore, the observed decrease in cytochrome P-450 concentration could reflect the direct inactivation of the hemoprotein or regulation of apoprotein production by cyclosporin and/or its metabolite(s). The possible relevance of the observations to cyclosporin nephrotoxicity is discussed.

Aniline Hydroxylase↗
PubMed1989

Improved use of buthionine sulfoximine to prevent cisplatin nephrotoxicity in rats.

Male Sprague Dawley rats were treated with buthionine sulfoximine (BSO) and cisplatin in different doses and schedules to optimize the chemoprotective effect of BSO against cisplatin nephrotoxicity. BSO at 4 mmol/kg, administered s.c. 2 h prior to cisplatin, resulted in normal blood urea nitrogen (BUN) levels in rats treated with 3 or 4 mg/kg cisplatin, and modestly, but significantly reduced the toxicity of cisplatin at 5 mg/kg. Administration of BSO (4 mmol/kg) at intervals ranging from 0 to 16 h prior to cisplatin (5 mg/kg) resulted in a significant reduction in BUN values. A BSO dose as low as 0.04 mmol/kg was found to be as effective as 4 mmol/kg against nephrotoxicity associated with cisplatin at 4 mg/kg. Repetitive injections of BSO (1 mmol/kg every 12 h, four times, beginning 2 h prior to cisplatin) significantly inhibited elevations of BUN associated with higher-dose cisplatin (6 mg/kg), whereas a single BSO injection of 4 mmol/kg was ineffective. The degree and duration of renal glutathione depletion was related to the dose of BSO. Renal glutathione content following 4 mmol/kg BSO was 38% of control at 2 h and 40% at 24 h; following 0.04 mg/kg, glutathione was 47% at 2 h and almost 100% at 24 h. Simultaneous in vitro administration of BSO did not inactivate cisplatin cytotoxicity as measured by the colony-forming ability of MBT-2 cells in soft agar. These data indicate that repeated injections of BSO, beginning prior to cisplatin administration, would improve the nephroprotective effect without compromising the chemotherapeutic efficacy of cisplatin. It is suggested that the ability of BSO to reduce cisplatin nephrotoxicity may not correlate with the degree of renal glutathione depletion and that the mechanism of action is unlikely to involve direct inactivation of cisplatin.

Animals↗
PubMed1989

Effect of systemic glutathione depletion by buthionine sulfoximine on sensitivity of murine bladder cancer to cytotoxic agents.

The effect of systemic glutathione (GSH) depletion on sensitization of bladder cancer cells to various antineoplastic agents was investigated using murine model, MBT-2. Subcutaneous injection(s) of buthionine sulfoximine (BSO) significantly depleted the GSH content in the tumor and organs. BSO pretreatment produced significant enhancement in the antitumor effect of cyclophosphamide (CY), though it failed to sensitize the tumors to doxorubicin hydrochloride (Adriamycin), cisplatin, mitomycin C, JM-8, methotrexate, vinblastine, and tumor necrosis factor. Mice tolerated cytotoxic agents alone and in combination with BSO except for cisplatin in combination with BSO. A 29 percent (4/14) mortality rate was observed in mice treated with BSO and divided schedule of cisplatin.

Animals↗
PubMed1989

Vasocystostomy: a model for studying male reproductive toxicity in the rat.

A nonsacrificial rat model has been developed which permits the easy collection and measurement of spermatozoa. The ductus deferens is anastomosed to the bladder (Vasocystostomy) and urinary sperm is collected daily. The correlation between testicular histology and sperm counts indicates that this model is reliable. Using this model we demonstrate inhibition of sperm production by fluoroacetate.

Anastomosis, Surgical↗
PubMed1989

Expression of blood group precursor T antigen as a prognostic marker for human bladder cancer treated by bacillus Calmette-Guerin and interleukin-2.

The relationship between T antigen expression in transitional cell carcinoma of the bladder and response to bacillus Calmette-Guerin plus interleukin-2 treatment was studied. A total of 25 patients received combined treatment with bacillus Calmette-Guerin and interleukin-2 at weekly instillations for 6 consecutive weeks and then monthly for 1 year. T antigen expression in all patients was studied before treatment. Of the patients 16 had positive T antigen expression in the tumors: 13 (81%) remained free of tumor for an average of 28 months, 3 had a noninvasive recurrence each at 8 to 27 months (mean 18 months) and all responded well to a repeated treatment cycle. Nine patients were negative for T antigen: 1 (11%) remained free of tumor for 11 months, while 8 had recurrence within 12 months. Of the latter 8 patients 2 had noninvasive recurrence each at 4 to 5 months but they responded to a repeated treatment cycle and remained free of tumor for 4 to 22 months (mean 13 months), 4 had subsequent repeated recurrences at 12 to 41 months (mean 22 months) and 2 had progression to deep invasion resulting in cystectomy at 11 to 12 months. Thus, the disease-free rate (continuous complete response) in patients with tumors positive for T antigen was 81%, while that in patients with tumors negative for T antigen was 11% (p less than 0.005, chi-square test). The over-all response rate in patients with positive and negative tumors to bacillus Calmette-Guerin and interleukin-2 treatment was 100 and 33%, respectively, and that for the total patients was 76%. T antigen may serve as a target recognition structure for effector cells generated by bacillus Calmette-Guerin plus interleukin-2 treatment. This study suggests that T antigen is useful to predict the response of bladder tumors to treatment with bacillus Calmette-Guerin and interleukin-2.

Aged↗
PubMed1989

Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3,885 patients.

The mortality rate for transurethral prostatectomy was 0.2 per cent in 3,885 patients reviewed retrospectively. The immediate postoperative morbidity rate was 18 per cent. Increased morbidity was found in patients with a resection time of more than 90 minutes, gland size of more than 45 gm., acute urinary retention and patient age greater than 80 years, and in the black population. Of the patients 77 per cent had significant pre-existing medical problems. Operative mortality, significant morbidity and hospital stay were reduced in comparison to studies done 15 and 30 years ago.

Age Factors↗
PubMed1989

Transurethral prostatectomy: practice aspects of the dominant operation in American urology.

In a national survey of all American urologists transurethral prostatectomy accounted for 38 per cent of the major surgical procedures performed by the respondents. They regarded the operation as complex and they believe achievement of proficiency requires that more be performed during residency training than any other urological operation. Furthermore, they assigned transurethral prostatectomy a significantly higher relative value than have medical economists doing research in the field of physician reimbursement. The effect of recent legislated congressional reductions in the allowable Medicare fees for transurethral prostatectomy is discussed along with the impact of these reductions on urological patient care and the American urologist. Practice patterns and geographic variations in the costs of transurethral prostatectomy also are considered.

Adult↗
PubMed1988

Cyclosporin-mediated increase in kidney glutathione and effects on gamma-glutamyl-cycle enzymes.

The unprecedented ability of cyclosporin A, when given for six days at a dose of 25 mg/kg/d or 50 mg/kg/d, to cause a marked and sustained increase in renal glutathione (GSH) concentration in rat kidney is described. This response was particular to the kidney insofar as the GSH concentration in the liver was not increased in response to a lower dose of cyclosporin and was decreased in the liver of animals treated with the higher dose of the drug. The increase in kidney GSH concentration did not appear to be due to an increased rate of production or to an inhibition of the degradation of the tripeptide. This suggestion is based on the finding that the activities of the GSH synthesis pathways, GSSG-reductase and gamma-glutamylcysteine synthetase, were unchanged or decreased, respectively, and those of the catabolic enzymes, GSH-peroxidase and gamma-glutamyltranspeptidase, were unchanged or increased, respectively. It is suggested that the elevation of renal GSH content in the face of diminished synthetic capacity and an apparent increased utilization may result from an enhanced uptake of GSH as the result of alterations caused by cyclosporin in the renal transport system.

Animals↗
PubMed1988

Interleukin 2 suppression of a murine bladder cancer implanted into kidney, bladder and skin; its organ specificity.

Little is known about organ associated tumor response to systemic interleukin 2 (IL2) therapy. The effect of IL2 on bladder cancer growth in the skin and in the genitourinary tract was investigated. C3H mice were implanted with the syngeneic transitional cell carcinoma, MBT-2, intradermally (i.d.), beneath the left renal subcapsular area, and in one experiment, simultaneously in the bladder. IL2 (human recombinant form; Biogen Research Co) was given i.p. at 5000 U thrice daily for 5 consecutive days commencing on Day 3, or for 10 to 11 days commencing on Day 10 with some doses omitted at signs of toxicity. For comparison, mice bearing 3-d and 10-d tumors in the skin and subcapsular kidney were treated with chemotherapy (cisplatin, 6 mg./kg. X 3; mitomycin C, 3 mg./kg. X 3; cyclophosphamide, 75 mg./kg. X 1). IL2 therapy mediated growth suppression of 10-d tumors in the genitourinary organs and skin at a similar rate. In contrast to IL2, systemic chemotherapy mediated tumor suppression in an organ specific manner; renal subcapsular tumors responded to the chemotherapy, whereas i.d. tumors were insensitive. Three-day tumors (both i.d. and renal subcapsular tumor) responded relatively well to each treatment compared to 10-d tumors. These data suggest that in systemic immunotherapy with IL2, anatomic location of the tumor is less important for inducing an antitumor response than in chemotherapy.

Animals↗
PubMed1988

Ineffectiveness of adoptive chemoimmunotherapy with lymphokine-activated killer cells, interleukin-2, and cyclophosphamide on palpable intradermal murine bladder cancer.

The effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells and human recombinant interleukin 2 (IL2), on palpable intradermal (i.d.) bladder tumor were studied. The murine transitional cell carcinoma MBT-2 was used in C3H mice. IL2 was given intraperitoneally at 5,000 U/injection three times a day for 5 consecutive days beginning on day 10. LAK cells were generated in vitro from normal splenocytes: 10(7)-10(8) LAK cells were transferred intravenously on day 10 and, in some experiments, also on day 13. IL2 alone, LAK cells alone (total 8 x 10(7], and both in combination showed little or no influence on intradermally growing MBT-2 tumors. Cyclophosphamide was also combined with adoptive immunotherapy (IL2 and LAK). CY (100 mg/kg, i.p. on day 9 or 10) alone was able to suppress i.d. MBT-2 growth significantly. The combination treatment of IL2 and LAK cells with CY caused additional tumor growth suppression in a manner dependent on the total number of LAK cells transferred. The amount of the additional tumor growth suppression was, however, relatively small when compared with CY plus IL2-treated groups. In comparison, experimentally induced 3-day and 10-day pulmonary metastases of MBT-2 cells were treated by the same protocol of IL2 and LAK cells but without CY. IL2 alone reduced the number of gross metastatic nodules in the lung. The addition of LAK cells to the IL2 almost entirely eradicated the 3-day metastatic nodules but was less effective against the 10-day metastases. The data suggest that adoptive immunotherapy with IL2 and LAK cells mediates tumor regression of micrometastases at a selected organ (lung), but is ineffective against the same tumor growing in the skin or in gross metastatic nodules. Host immune suppression by CY was not beneficial in this model in creating a successful therapeutic effect of LAK cells and IL2.

Animals↗
PubMed1988

Eradication of palpable intradermal murine bladder tumors by systemic interleukin-2 and cyclophosphamide in C3H mice.

The effect of cyclophosphamide on interleukin-2 (IL-2) therapy was investigated using the intradermal MBT-2 tumor in C3H mice. Human recombinant IL-2 (Biogen) was given intraperitoneally at doses ranging from 5,000 to 30,000 U, three times a day for 5 or 11-13 consecutive days beginning on day 10 after tumor implantation. When IL 2 was given alone, mice could not tolerate greater than 5 days of 5,000 U IL 2/injection: Administration of 10,000 and 15,000 U/injection of IL-2 for 5 days resulted in 64% (9 of 14) and 100% (14 of 14) mortality, respectively. Chemotherapeutic agents (cisplatin at 6 mg/kg or JM-8 75 mg/kg) and daily administration of cortisone acetate (75 mg/kg) partially protected mice from IL-2-induced toxic deaths. Coadministration of mannitol showed no protective effect. The combination of IL-2 and CY at 75 or 100 mg/kg, however, dramatically reduced the mortality induced by IL-2 and made it possible to escalate the dose and long-term administration of IL-2. Combination administration of 75 mg/kg CY with 15,000 U/injection of IL-2 for 11-13 days caused tumor regressions and resulted in a 66% (8 of 12) cure rate.

Animals↗
PubMed1987

Efficacy of antitumor chemotherapy in C3H mice enhanced by the antiangiogenesis steroid, cortisone acetate.

The effect of "antiangiogenesis" therapy using cortisone acetate (CA) with or without heparin on tumor growth as well as in combination with chemotherapy was investigated. C3H mice were implanted intradermally with N-[4-(5-nitro-2-furyl)-thiazolyl]formamide induced undifferentiated transitional cell carcinoma, MBT-2, in the right flank. The treatment was initiated 9 to 10 days after tumor inoculation. Daily injections of CA (250 mg/kg s.c.) suppressed tumor growth significantly in a dose dependent fashion. Administration of heparin (Elkins-Sinn) at the concentration of 200, 400, or 1000 units/ml in drinking water for 3 to 6 days was neither additive nor detrimental to the effect of CA. Chemotherapy was combined with CA; 3 days of administration of 250 mg/kg of CA in tapering doses was used. The chemotherapeutic agent was injected once 24 h before the initial CA. Combinations of chemotherapy (Adriamycin, 2.5-7.5 mg/kg i.v; cisplatin, 3-9 mg/kg i.p.; cyclophosphamide, 50-150 mg/kg i.p.; cis-(diammino)(1,1-cyclobutanedicarboxylate)platinum(II) (JM-8), 60-150 mg/kg i.p.; mitomycin C, 3-4.5 mg/kg i.p.) with CA showed additive suppression of tumor growth. Mice tolerated chemotherapy alone, CA alone, and both in combination. CA combined with JM-8 was not tolerated. Mice tolerated 100 to 150 mg/kg of JM-8, whereas the addition of CA to JM-8 resulted in a 66% (6 of 9) to 89% (8 of 9) mortality rate. CA at a concentration of 5 and 25 micrograms/ml showed no direct cytotoxic activity against MBT-2 cells in vitro. However, 3 days of administration of 250 mg/kg of CA inhibited tumor angiogenesis generated by MBT-2 cells in C3H mice using a dorsal air sac assay. The data suggest that CA alone inhibits tumor angiogenesis in C3H mice and that antiangiogenesis therapy enhances the antitumor efficacy of chemotherapeutic agents without increasing host toxicity (except for JM-8).

Animals↗
PubMed1987

Inhibition of cisplatin-induced nephrotoxicity in rats by buthionine sulfoximine, a glutathione synthesis inhibitor.

DL-Buthionine-(S,R)-sulfoximine (BSO), a glutathione-depleting agent, was found to diminish the nephrotoxic effect of cisplatin (cis-diamminedichloroplatinum). Pretreatment of rats with BSO (4 mmol/kg s.c.) 2 h prior to cisplatin, either as a single dose of 5 mg/kg or at a daily dose of 2.5 mg/kg for 3 consecutive days, resulted in diminished elevations of plasma BUN concentration and decreased cisplatin-induced inhibition of renal gamma-glutamylcysteine synthetase and gamma-glutamyl transpeptidase activity measured 6 days following treatment. Administration of BSO prior to cisplatin at 7.5 mg/kg did not significantly alter the effect of cisplatin on either BUN concentration or enzyme activity. The influence of BSO pretreatment on the antitumor activity of cisplatin was studied using implantation of a murine bladder cancer (MBT-2) in C3H mice. Pretreatment of mice with BSO (5 mmol/kg) did not influence cisplatin antitumor efficacy.

Animals↗
PubMed1987

Zinc sulfate therapy for infertile male with or without varicocelectomy.

One hundred one men were treated for infertility with 440 mg of zinc sulfate daily for sixty days to two years. All subjects demonstrated low seminal plasma zinc concentrations prior to treatment. Patients were divided into two groups: group [Zn], 65 subjects who underwent zinc therapy alone and group [Var/Zn], 36 subjects who received zinc sulfate therapy after varicocelectomy. In both groups seminal zinc levels were significantly higher (P less than 0.05 and P less than 0.01, respectively) two months after the initiation of zinc therapy. There were no significant changes in sperm count or motility for the [Zn] patients. However, group [Var/Zn] showed a significant increase (P less than 0.05) of sperm motility at two months and twelve months after starting zinc sulfate therapy. We separated the [Var/Zn] patients into two sub-divisions: those who impregnated their wives after therapy, and those who remained infertile despite treatment. Only those patients who impregnated their wives showed a significant (P less than 0.05) increase in sperm motility two months after the initiation of zinc therapy. Those patients of the [Var/Zn] group who remained infertile despite treatment showed a significant increase (P less than 0.05) in sperm motility after twelve months of therapy. Of the [Zn] patients 27.7 per cent (18) successfully impregnated their wives, while the [Var/Zn] patients exhibited a pregnancy rate of 50 per cent (18 patients). These data indicate that zinc sulfate therapy for patients with low seminal zinc concentrations may be an effective treatment for infertile patients especially after varicocelectomy.

Humans↗