Rapid rise of serum testosterone following discontinuation of long term treatment of prostate carcinoma with an LHRH-agonist.
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Buserelin↗
Biomedical subjects
W Kreis
Publications and source records attributed to W Kreis.
Adrenal steroid levels in castrated men with prostatic carcinoma treated with aminoglutethimide plus hydrocortisone.
Monthly serum dehydroepiandrosterone sulfate, androstenedione, testosterone, dihydrotestosterone, and free testosterone levels were measured in 94 of 129 patients with castration resistant prostatic carcinoma treated on a clinical protocol with aminoglutethimide (1000 mg/day) plus hydrocortisone (40 mg/day) Base-line steroid levels were not found to be age related. Therapy reduced the median levels of all monitored steroids but this suppression was not uniform. Although 87% of dehydroepiandrosterone sulfate levels were suppressed compared to base-line measurements, only 52% of androstenedione and 49% of testosterone levels were reduced. Androstenedione levels in 34% of patients actually rose to greater than twice base-line levels with similar but less frequent rises seen in testosterone, free testosterone, and dihydrotestosterone levels. The highest testosterone level measured was 190 ng/ml. Neither the cause, the deviation, nor the clinical significance of the androgen rise seen in these patients was established. Therapy with aminoglutethimide plus hydrocortisone as administered in this study may not uniformly achieve the objective of suppressing adrenal androgen production.
Aminoglutethimide↗
Zoladex: a sustained-release, monthly luteinizing hormone-releasing hormone analogue for the treatment of advanced prostate cancer.
Zoladex, a sustained-release luteinizing hormone--releasing hormone (LHRH) analogue administered by subcutaneous injection every 28 days, was evaluated at three dose levels in 46 men with untreated advanced prostate cancer. All three Zoladex doses yielded similar endocrinologic effects. After initial transient increases in serum luteinizing hormone, follicle-stimulating hormone, and testosterone concentrations, serum testosterone was suppressed uniformly to castration levels within 22 days. At a median follow-up of 41 weeks, Zoladex had maintained persistent suppression of serum testosterone. Measurements of serum Zoladex levels indicated that release of the drug from the injected depot was sustained over a period of 1 month and that there was no drug accumulation as evaluated over an initial 3-month period. No antibodies to Zoladex were detected. Tumor regression rates and side effects with Zoladex therapy were similar to those reported with daily injections of subcutaneous LHRH therapy. Signs and symptoms consistent with a brief tumor flare after the first injection of the LHRH analogue were noted in eight (17%) of the study entrants. Spinal cord compression was observed in two patients within 1 week from the onset of therapy. Zoladex is considered to be an effective, sustained-release LHRH analogue for the treatment of patients with prostate cancer.
Adenocarcinoma↗
Clinical pharmacology of vinzolidine.
Vinzolidine (VZL), a new semisynthetic vinca alkaloid, was studied by using 3H-labeled VZL administered PO in four patients. At single doses from 1.5 to 36.5 mg/m2 (0.034-0.919 mg/kg) radioactivity was rapidly absorbed with a half-life of absorption of 1 h and a peak at 4 h. Plasma decay of radiolabel followed a biphasic pattern with an alpha half-life of 10.48 h and a beta half-life of 172 h. The apparent plasma clearance was dose-dependent. The total radiolabel recovered was 52.9% +/- 11.4% of the administered label, with 90% in the feces. HPLC analysis revealed that in all extracted plasma, urine, and feces the predominant material was unchanged VZL. Several metabolites were observed but not identified.
Dose-Response Relationship, Drug↗
Pharmacokinetics of low-dose 1-beta-D-arabinofuranosylcytosine given by continuous intravenous infusion over twenty-one days.
The pharmacokinetic parameters of low dose 1-beta-D-arabinofuranosylcytosine (ara-C) infusions were studied in 11 patients, 6 males and 5 females, with a mean age of 68.5 +/- 13.8 (SD) years. The drug was infused to 4 patients with pre-leukemia (refractory anemia with excess blasts), 5 patients with acute myelogenous leukemia, and 2 patients with secondary leukemia due to chemotherapy, at a dosage of 20 mg/m2/day over 21 days. The patients' blood and urine were analyzed for ara-C content by radioimmunoassay. Mean steady state plasma levels of 7.7 +/- 4.7 ng/ml (31.7 +/- 19.3 nM) (n = 189) and a range 0.6 (2.5 nM) (lower limit of assay) to 29.7 ng/ml (122.1 nM), with significant inter- and intra-patient variations, were reached within about 2.7 h. The plasma levels of ara-C decreased rapidly, with a t1/2 alpha of about 12 min following discontinuation of the infusion, followed by a very slow t 1/2 beta of about 19 h. Other parameters (mean values of 10 or 11 patients) were: area under the curve, 182.1 +/- 64.8 ng X day/ml; total body clearance, 188.7 +/- 54.8 liters/h; renal clearance, 3.1 +/- 1.4 liters/h; volume of distribution at steady state, 53,913 +/- 17,626 liters; and recovery of ara-C in urine, 1.43 +/- 0.69% (n = 226) of daily administered ara-C. A linear relationship was observed with administered dose when the mean plasma levels of our study were compared with the ones reported for conventional ara-C infusions. Plasma clearance was comparable to that observed in conventional dose, when the observed values were extrapolated to the dose administered in this study.
Aged↗
Preclinical evaluation of acid products for treatment of solid experimental skin tumors in mice.
The effect of nitric acid preparations on five different solid experimental tumors in mice was studied. None of these highly malignant tumors was eradicated by any of the acid preparations studied, although differences in reactivity were noted between preparations in some models.
9,10-Dimethyl-1,2-benzanthracene↗
Effects of 5-fluorouracil and 2 alpha-methyldihydrotestosterone propionate on the growth of human breast carcinoma MCF-7 in vitro.
5-Fluorouracil (5-FU) and 2 alpha-methyldihydrotestosterone propionate (MDTP) have effectively induced complete regressions of induced rat mammary carcinomas; in combination, regressions were additive and synergistic. Present aims were to determine whether similar antitumor effects were obtainable with a human mammary carcinoma, MCF-7, and to affirm the synergism of 5-FU and MDTP. After incubation in vitro for 3 days and exposure to drug for another 2 days, cell counts and/or determinations of total cell protein revealed growth inhibitions of 16-87% by 5-FU at 130-1300 micrograms/ml and 16-94% by MDTP at 0.36-360.5 micrograms/ml. Combinations of 5-FU and MDTP at the same inhibitory doses (ID) yielded approximately additive growth inhibitions. Algebraic and geometric (isobole) methods of analyses showed that these inhibitions were additive or synergistic, depending on the iso-effective dose used. Precursor incorporation into macromolecules also showed approximately additive effects for MCF-7 cells treated with 5-FU and MDTP, each at ID15. These data demonstrate significant additive growth-inhibitory activity of 5-FU and MDTP in combination against MCF-7 in vitro, thus affirming their antitumor effects in vivo.
Androstanols↗
Phosphorylation of selected substrates by semipurified cytoplasmic kinases of three P815 murine leukemias exhibiting collateral sensitivity (P815/TG), sensitivity (P815) or resistance (P815/ARA-C) to 1-beta-D-arabinofuranosylcytosine.
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Animals↗
In vitro metabolism of 1-beta-D-arabinofuranosylcytosine and 1-beta-2'-fluoroarabino-5-iodocytosine in normal and herpes simplex type 1 virus-infected cells.
Phosphorylation of 1-beta-D-2'-F-arabino-5-iodocytosine (FIAC), a newly synthesized pyrimidine nucleoside with potent antiherpesvirus activity, was compared with that of its parent compound, 1-beta-D-arabinofuranosylcytosine (ara-C). While ara-C was phosphorylated extensively by homogenates of normal, rapidly proliferating mouse tissues, FIAC was a poor substrate for the nucleoside kinase occurring in such normal tissues. With cell homogenates of noninfected Vero cells, thymidine (TdR) was phosphorylated about fifty and twenty times more efficiently than FIAC and ara-C, while infection of Vero cells with Herpes Simplex Virus Type 1 (HSV-1) resulted in a 23-fold increase of TdR- and a 1270-fold increase of FIAC phosphorylation. In contrast, phosphorylation of ara-C was increased only by a factor of 2.6. While the reaction products obtained with homogenates of normal mouse tissues were 5'-mono-, di- and triphosphates of ara-C and FIAC, the reaction products with noninfected and infected Vero cell homogenates were predominantly monophosphates. In contrast, TdR was efficiently phosphorylated to its 5'-mono-, di- and triphosphates by such homogenates. In intact HSV-1-infected Vero cells. FIAC was rapidly taken up and phosphorylated to FIACMP and to an as yet unidentified metabolite. In contrast, TdR was taken up and phosphorylated to 5'-mono-, di- and triphosphates and ara-C was taken up moderately but metabolized poorly to its 5'-mono-, di- and triphosphates. Thus, in normal tissues, FIAC was a poorer substrate than ara-C for nucleoside kinases, but in intact HSV- 1-infected Vero cells FIAC was efficiently phosphorylated and thus behaved like a TdR analog, except that it was phosphorylated only to the 5'-monophosphate and a hitherto unidentified metabolite. The greatly increased phosphorylation of FIAC by HSV-1-infected Vero cells probably accounts, at least in part, for its great selectivity of action.
Antiviral Agents↗
Inhibition of thymidylate synthase by hydroxyurea in rapidly proliferating P815 mastocytoma cells.
The incorporation of [14C]deoxycytidine, [3H]deoxyuridine, and [3H]thymidine, respectively into pyrimidine bases of DNA has been measured in rapidly proliferating P815 mouse mastocytoma cells in the presence of hydroxyurea. The incorporation of [14C]deoxycytidine-derived radioactivity into DNA cytosines is increased when compared to the incorporation into DNA thymines. The [3H]deoxyuridine-derived radioactivity is incorporated solely into DNA thymines and this incorporation is inhibited by hydroxyurea in a dose-dependent manner. This suggests an inhibitory effect of hydroxyurea on the thymidylate synthase which was proved in experiments in which the conversion of deoxyuridine monophosphate into deoxythymidine monophosphate catalysed by a crude enzyme preparation from P815 cells was inhibited in the presence of hydroxyurea. Enzymatic DNA methylation as measured by the conversion of incorporated [14C]deoxycytidine into 5-methylcytosines was not affected by hydroxyurea.
Animals↗
Deoxycytidine and deoxythymidine kinase activities in plasma of mice and patients with neoplastic disease.
In C57BL x DBA/2 F1 (hereafter called BD2F1) mice inoculated with P815 neoplasms and in AKR mice with spontaneously developing leukemia, significant amounts of plasma deoxycytidine and thymidine kinase activities were detected in advanced disease. Undetectable or low levels of such kinase activities were observed in normal BD2F1 and in control AKR mice. Initial studies with leukemia patients revealed increased amounts of plasma deoxycytidine and thymidine kinase activities correlating favorably with the peripheral white blood cell counts. Initial studies with small numbers of patients with solid tumors revealed significant activities of both kinases in plasma of patients with four different cancers. Healthy volunteers revealed enzyme activities only insignificantly above background.
Adolescent↗
High pressure liquid chromatographic determination of cyclosporin-A in human plasma.
Periodic monitoring of plasma drug concentrations has been suggested as a means whereby the toxicity of Cyclosporin A (CyA) can be reduced in patients undergoing bone marrow transplantation. We have developed a sensitive and specific method for the determination of CyA in plasma using reverse phase high pressure liquid chromatography (HPLC). Cyclosporin D was used as the internal standard. The lower limits of detection are 100 ng/ml in biological fluids and 20 ng per injection onto the column. We have analyzed plasma samples from patients who received CyA at doses which ranged from 8 to 15 mg/kg/day. Although all patients experienced toxic or therapeutic effects, plasma concentrations of CyA were consistently less than 100 ng/ml when analyzed by this method. We conclude that analytical methods currently available for the detection of CyA are unsuitable for the monitoring of patients who receive this agent.
Chromatography, High Pressure Liquid↗
Cyclosporin A in leukaemia.
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Acute Disease↗
Effect of nutritional and enzymatic methionine deprivation upon human normal and malignant cells in tissue culture.
Human embryonic lung fibroblasts (F-136-35-56) capable of growing in medium containing DL-homocysteine instead of L-methionine and human acute lymphoblastic leukemia cells (CCRF-HSB-2) with absolute methionine requirement exhibited dose-dependent growth inhibition when semipurified L-methionine-degrading enzyme (L-methioninase, EC 4.4.1.11) was added to the tissue cultures. When D-homocystine was added to the cultures together with L-methioninase (0.1 units/ml, which completely degraded the available L-methionine in tissue culture), the F-136-35-56 cells continued to grow whereas the CCRF-HSB-2 cells were completely inhibited. In mixed cultures of the two cell lines with added L-methioninase + D-homocystine or L-methioninase + L-homocysteine thiolactone, the normal fibroblasts grew and synthesized DNA vigorously, whereas the lymphocytic malignant cells lost their viability completely and died within 3 to 4 days.
Carbon-Sulfur Lyases↗
Cyclosporins: immunosuppressive agents with antitumor activity.
Initial screening of the 2 recently developed immunosuppressive agents, cyclosporin A and cyclosporin C, in 11 murine transplantable neoplasms revealed significant increase of lifespan with long-term survivors after i.p. injection to the ascites tumors, Taper liver, Sarcoma 180J and Ehrlich.
Animals↗
Distribution pattern and enzymic hypermethylation of inverted repetitive DNA sequences in P815 mastocytoma cells.
A specific class of DNA sequences, the inverted repetitive sequences, forms a double-stranded structure within a single linear polynucleotide chain in denatured DNA. The reassociation process is unimolecular and occurs very fast. Quantitative analyses have shown that in mouse P815 cells these sequences comprise about 4% of the nuclear DNA and are interspersed within sequences of other degrees of repetitiveness. After labeling the cells with L-[Me-3H]methionine and [14C]deoxycytidine, relative rates of enzymic DNA methylation were computed on the basis of radioactivities found in pyrimidine residues of the nuclear DNA. The results indicate that in P815 cells, DNA of inverted repetitive sequences is methylated to a level about 50% higher than the normal repetitive DNA sequences and to about 300% higher than the unique and intermediary intermediatry sequences. The biological function of the inverted repetitive sequences, as well as of the role of enzymic methylation of DNA remains unknown.
Animals↗
Comparison of a water-soluble and a water-insoluble podophyllotoxin derivative in murine neoplasms.
Comparison of a water-soluble (27-487) with a water-insoluble (VP-16-213) podophyllotoxin derivative in seven murine neoplasms revealed slight therapeutic superiortiy of VP-16-213 but also slightly greater toxicity when compared with 27-487. A strikingly good response of the Taper liver tumor to both compounds was observed, providing further incentive to the use of podophyllotoxin derivatives in human hepatomas.
Animals↗
Tumor therapy by deprivation of L-methionine: rationale and results.
Published reports indicate that normal rodent cells can grow in medium containing either L-methionine or L-homocysteine, whereas malignant rodent cells have an absolute requirement for L-methionine. Our studies with two normal human cell lines (fetal lung fibroblasts and bladder epithelial cells) exhibit equal growth in media containing either L-methionine or L-homocysteine. The same is true for five malignant human cell lines (carcinoma of the cervix [HeLa], adenocarcinoma of the breast [AlAb], acute lymphoblastic leukemia [MOLT-3], Wilms' tumor [SK-NEP-1], and reticulum cell sarcoma [T-77], whereas four other malignant cell lines (adenocarcinoma of the breast [SK-BR-2-III], the two lymphoblastic leukemias [CCRF-HSB-2 and CCRF-SB], and a neuroblastoma [SK-N-MC]) have absolute requirements for L-methionine. Two malignant cell lines, an adenocarcinoma of the lung (A549) and an adenocarcinoma of the pancreas (Capan-1), showed restricted growth under the experimental conditions used. L-Methionlinase (L-methionine-alpha-deamino-gamma-mercaptomethane-lyase, EC 4.4.1.11) at a concentration of 0.1 unit/ml leads to complete growth inhibition of cell cultures of both the normal human fetal lung fibroblasts (F-136-35-56) and the acute lymphoblastic leukemia (CCRF-HSB-2). L-Homocysteine-thiolactone in medium containing L-methioninase could partly "rescue" the normal but not the malignant cells.
Animals↗