Biomedical subjects

B Hartley-Asp

Publications and source records attributed to B Hartley-Asp.

At least 19 recordsLinked to original sources

PubMed1998

Differential uptake of estramustine phosphate metabolites and its correlation with the levels of estramustine binding protein in prostate tumor tissue.

Estracyt (EMP) has been used for the treatment of hormone refractory prostate cancer for many years. Recently, new data from combination studies have given rise to new interest in this old drug. Explanations for the synergy found in the clinic are many, but one major factor may be the previous indication that the drug accumulates in the prostate tumor. We have, therefore, examined the level of the four metabolites, estromustine (EoM), estramustine (EaM), estrone, and estradiol in the tumor and serum of 14 patients with T2 and T3 prostate cancer receiving a single i.v. dose of 600 mg of EMP, about 12 h before radical prostatectomy. Because it has been suggested that the uptake into the prostate tumor is due to binding to the estramustine binding protein (EMBP), we have in addition measured the level of EMBP in the prostate tumor tissue. The main serum and tissue metabolite in all patients was EoM followed by EaM, estrone, and estradiol. The levels for EoM ranged from 63.8-162.8 ng/ml in the serum and from 64.8-1209 ng/ml in the prostate tumor, resulting in a mean ratio for serum to tumor of 1:5. The levels for EaM ranged from 8.3-51.4 ng/ml in the serum and 73.9-563.4 ng/ml in the tumor, giving a mean ratio for serum to tumor of 1:13. The levels of EMBP were higher in T3 tumors than in T2 tumors, 54.1 and 40.7 ng/g tissue, respectively. A significant correlation was found between the levels of EaM (r = 0.60) and the levels of EMBP in the tumor. These data demonstrate that 12 h after a single i.v. dose of 600 mg of EMP the levels of the cytotoxic metabolites EoM and EaM are substantially higher in the tumor than in the serum of the same patient and that a correlation exists between the levels of EaM in the tumor and the levels of EMBP. Thus, this supports the hypothesis that the EMBP is responsible for the retention of EoM and EaM in the prostate tumor.

Aged↗

PubMed1997

Interaction of estramustine with tubulin isotypes.

The interaction of the antimitotic agent estramustine with bovine microtubule proteins and purified tubulin was investigated. Direct photoaffinity labeling of microtubule protein with [14C]estramustine resulted in the labeling of both alpha- and beta-tubulin, and this was inhibited with unlabeled estramustine in a dose-dependent manner. [14C]Estramustine was incorporated into both the soluble and polymerized forms of tubulin. The affinity constant for estramustine binding to tubulin was determined by equilibrium dialysis to be 23 +/- 5 mM. Estramustine did not affect [3H]vinblastine binding, and vinblastine had no effect on direct labeling with [14C]estramustine. Both rhizoxin and paclitaxel decreased the covalent labeling of tubulin with [14C]estramustine in a dose-dependent fashion and were noncompetitive inhibitors of the binding of estramustine to tubulin. The binding of colchicine to tubulin was not inhibited by estramustine as detected by fluorescence and DEAE filter assays. The estramustine binding site on tubulin is therefore distinct from that of colchicine and vinblastine and may at least partially overlap with the binding site for paclitaxel. In both bovine brain microtubules and cytoskeletal proteins from human prostatic carcinoma cells, the incorporation of [14C]estramustine into the beta III isotype of tubulin was found to occur with a reduced efficiency compared to that of the other beta-tubulin isotypes and alpha-tubulin. Since this isotype is overexpressed in estramustine resistant human prostate carcinoma cells, these results indicate that beta III-tubulin may play a role in the response to the effects of estramustine.

Animals↗

PubMed1997

Assessment of hormone refractory prostate cancer.

OBJECTIVES: To define guidelines for the assessment of treatment in patients with hormone-refractory prostate cancer (HRPC). METHODS: In the light of modern research, and taking new treatment options into account, the Committee essays to specify different categories of patients entering clinical trials, and to define response criteria and those endpoints that are relevant in phase III studies and in short-term follow-up. RESULTS: HRPC comprises a range of disease states with varying responsiveness to therapy and length of survival. Patients with progression as evaluated by increasing prostate-specific antigen (PSA) values alone have a more favorable prognosis than those presenting with increasing tumor spread. In the assessment of these patients, the modes of previous therapy and the kind of tumor progression must be taken into account. The benefit of treatment of HRPC is often modest. While duration of survival remains the main and ultimate endpoint, the means of measuring short-term responsiveness to therapy are limited. A minority of patients have measurable tumor lesions. Decrease of PSA or other biochemical tumor markers may indicate depression of the tumor activity, but is not always associated with prolongation of survival. A variety of new treatments in HRPC are being investigated. They affect measurable tumor parameters in different ways. CONCLUSIONS: When a new agent is to be tested, it is important to measure all possible parameters before deciding which particular ones are appropriate for future investigations of this agent. In symptomatic patients, evaluation of subjective parameters, for example, relief of pain or improvement of performance status, is often the most reliable measure of treatment effect. However, these parameters should be clearly defined.

Antineoplastic Agents, Hormonal↗

PubMed1997

Anti-angiogenic treatment with linomide as adjuvant to surgical castration in experimental prostate cancer.

PURPOSE: Escape from "castration inhibition," be it surgical or chemically induced, is still the major problem in prostate cancer treatment. New agents that can be given as adjuvant therapy are needed. Linomide has demonstrated both anti-tumor and anti-angiogenic activity with little toxicity in the Dunning R-3327 rat prostate tumor system. Therefore it was deemed essential to study the efficacy of this drug in the adjuvant situation. MATERIALS AND METHODS: Linomide, roquinimex, was administered 3 times a week i.p. alone or in conjunction with castration to rats bearing the Dunning R-3327 PAP rat prostate tumor and its effect on tumor growth analyzed. Similar experiments, in which Linomide 25 mg./kg./day was given in the drinking water were carried out in rats with the Dunning R-3327 G tumor. The effect of treatment on blood vessel density and blood flow in the tumor was also assessed using an image analysis system. RESULTS: Linomide, 2.5 & 40 mg./kg., administered from the day after castration inhibited the regrowth of the Dunning R-3327 PAP tumors In addition, Linomide 40 mg./kg. administered after tumor regrowth occurred following castration(week 10) inhibited further tumor growth. Inhibition of tumor regrowth after castration was also found in the Dunning G tumor. When Linomide treatment was stopped regrowth of the tumors occurred, either in the same animal or on transplantation to new intact hosts, demonstrating that the tumor cells were still viable. Tumor blood vessel density was decreased both after castration and Linomide treatment alone, 40 and 32% respectively. On combination of castration and Linomide a 60% decrease in blood vessel density was found. This was significantly different from either of the two treatments given alone. The enhancement on combining castration and Linomide was confirmed by a further decrease in blood flow, from 19 and 22 to 12 ml. per minute/gm. tissue respectively. CONCLUSIONS: Linomide, an anti-angiogenic drug, inhibits escape from "castration inhibition".

Animals↗

PubMed1996

Chromosome aberrations and pharmacokinetics in patients receiving tauromustine as either a single or a repeated dose.

Tauromustine (TCNU) is an exploratory drug that has demonstrated activity in various solid tumors. We examined chromosome aberrations and plasma levels of the drug in two groups of patients receiving either a single dose of 130 mg/m2 or 40 mg/m2 on 3 consecutive days. Peak plasma concentrations (mean +/- SD) were obtained at a similar time after both treatments, i.e., at 38 +/- 25, 32 +/- 24, 28 +/- 14, and 40 +/- 26 min after administration of 130 mg/m2 on day 1 and after that of 40 mg/m2 on days 1, 2, and 3, respectively. In addition, the cumulative area under the curve (AUC value) determined after administration of 40 mg/m2 x 3 was similar to that noted after treatment with a single dose of 130 mg/m2, i.e., 180 and 179 micrograms min ml-1, respectively. Both treatments induced chromosome aberrations (CAs) in peripheral blood lymphocytes. A dose-dependent increase in the number of CAs was found, with 40 mg/m2 producing 5.5% CAs and 130 mg/m2 yielding 20.9% CAs at 24 h after treatment. In addition, although the drug concentration declined to a level under the detection limit between the daily treatments, drug-induced chromosome damage was cumulative, with the 90-min values increasing from 4.8% on day 1 to 14.3% CAs on day 3. In individual patients, no correlation was found between CAs and kinetic parameters; however, the total mean CA yield was in agreement with the total drug exposure (CAs, 14.3% and 14.6%, AUC 180 +/- 62.8 and 179 +/- 115 micrograms min ml-1, respectively.

Antineoplastic Agents↗

PubMed1995

The urokinase inhibitor p-aminobenzamidine inhibits growth of a human prostate tumor in SCID mice.

Malignant cells possess a high degree of proteolytic activity in which the plasminogen activator system plays an important role. An increased expression of urokinase type plasminogen activator (uPA) is of significance for degradation of the extracellular tumor matrix, facilitating invasiveness and growth. Inhibition of the active site of uPA makes it possible to evaluate the significance of uPA in tumor growth. We report here experiments on a uPA-producing human prostate xenograft (DU 145) using a competitive inhibitor of uPA, p-aminobenzamidine. In vitro experiments with DU 145 cells showed that p-aminobenzamidine caused a dose-dependent inhibition of uPA activity. DU 145 cells were inoculated s.c. in SCID mice and, once tumors were established, treatment with p-aminobenzamidine added to drinking water was started and lasted for 23 days. Mice receiving 250 mg/kg/day of p-aminobenzamidine showed a clear decrease in tumor-growth rate compared to the non-treated mice, resulting in 64% lower final tumor weight. In addition, uPA-antigen levels in the membrane fractions of DU 145 tumors from p-aminobenzamidine-treated mice were found to be decreased by 59%. We also show that p-aminobenzamidine has an anti-proliferative effect in cell culture at low cell number, correlating with a dose-dependent decrease in uPA production. In conclusion, we show that a low-molecular-weight uPA-inhibitor, p-aminobenzamidine, has a growth-inhibitory effect on a solid uPA-producing tumor.

Adenocarcinoma↗

PubMed1995

Differential expression of uPA in an aggressive (DU 145) and a nonaggressive (1013L) human prostate cancer xenograft.

Prostate cancer has a slow growing noninvasive phase, but, in general, is invasive on diagnosis. An initial step in the invasion of surrounding normal tissue is the activity of proteolytic enzymes such as components of the plasminogen activator system (PA). In cell culture, the primary human prostate cancer cell line 1013L expressed no urokinase type-PA (uPA), while DU 145, a cell line derived from a metastatic lesion, expressed high levels of uPA. The DU 145 cells grew easily as xenografts but the establishment of 1013L in the SCID mice was possible only with the aid of a gelatin sponge (Spongostan). The latency period was 42-64 days, followed by a slow growth phase before a fast growth phase occurred. This fast growth phase was characterized by rapid degeneration of tumor tissue, while high proliferation occurred around the blood vessels. On serial transplantation of tumor material, the growth pattern was similar. Furthermore, the 1013L tumor was encapsulated by connective tissue and no invasiveness could be detected. We found that 1013L tumor homogenates had hardly detectable levels of uPA, i.e., 300-fold lower than we found in the invasive prostate xenograft DU 145. In addition, no expression of uPA was found in the plasma of 1013L tumor-bearing mice whilst uPA antigen was detected in the plasma of DU 145 tumor-bearing mice. In conclusion, the 1013L cell line, which exhibits a nonaggressive pattern, could be a good model for studying progression of prostate cancer to a more aggressive phenotype in vivo and in vitro.

Animals↗

PubMed1995

Inhibition of tumor angiogenesis and the therapeutic ability of linomide against rat prostatic cancers.

Linomide, a quinoline-3-carboxamide, has growth-inhibitory effects against a series of Dunning R-3327 rat prostatic cancers in vivo [Ichikawa et al.: Cancer Res 52:3022-3028, 1992]. In addition, we have demonstrated that daily linomide treatment can inhibit angiogenic responses in nontumor-bearing rats and reduce tumor blood flow in tumor-bearing rats [Vukanovic et al.: Cancer Res 53:1833, 1993]. In the present study we have demonstrated that the reduced tumor blood flow is due to linomide's ability to inhibit tumor angiogenesis, as documented by decreased number of blood vessels in prostatic carcinomas growing in rats treated daily with linomide. Due to linomide's ability to inhibit tumor angiogenesis, and since tumor angiogenesis is required not only for the growth of the primary cancer but also for its ability to metastasize, the effect of linomide on metastasis was directly tested using a quantitation metastasis assay. These in vivo experiments demonstrated that daily linomide treatment decreased by 3-fold the extent of dissemination of cancer cells to the lungs. To test if this antimetastatic response is due to direct effects of linomide on the metastatic cells themselves as well as an induced effect upon inhibition of tumor angiogenesis, additional studies were performed. These studies demonstrated that linomide is not converted in vivo to metabolite(s) which are directly cytotoxic or cytostatic to the prostatic cancer cells themselves. These studies also demonstrated that linomide does not decrease the attachment, migration, or invasive abilities of metastatic cancer cells. These results suggest that the major mechanism for the antitumor and antimetastatic effects of linomide is via its inhibition of tumor angiogenesis. Additional studies have demonstrated that in vivo linomide treatment results in the apoptotic death of thymocytes. This cytotoxic effect is not required for linomide's antitumor effect, nor is it due to elevated plasma levels of glucocorticoid.

Alkylation↗

PubMed1995

Quantitative angiogenesis in a syngeneic tumor spheroid model.

The aim of this work was to develop a system for noninvasive, in vivo, and in situ study of tumor angiogenesis in awake mice. Tumor spheroids were prepared from Lewis lung carcinoma cells prelabeled with methylrhodamine. A transparent chamber consisting of two titanium frames was implanted into the dorsal skin of CB6 mice. One layer of the skin was removed in a 15-mm area and covered with a coverslip. A few days later, the coverslip was removed and one to three tumor spheroids (diameters, 500-900 microns) were placed over the upper tissue layer. The selected fields were recorded under trans- and epi-illumination using video microscopy. Separate fluorescence filter sets were used to visualize the FITC-labeled plasma and the rhodamine-labeled tumor spheroids. The dual labeling technique allowed precise identification of the tumors and the study of tumor and microvessel growth for up to 14 days. The tumor area and morphometric parameters of tumor vessels were measured from recorded images. After implantation, tumor cells formed well-defined tumor foci. Venular and capillary dilation and tortuosity were observed in the surrounding tissue 1-2 days after implantation, followed by the appearance of buds and sprouts. After that, vascular networks developed around and within the spheroid. During the first week, angiogenesis was very intense: at Day 6, vascular density and tumor area reached 81 and 19% of their respective maximum values. Vascular densities at Days 3, 6, 10, and 14 were 106 +/- 59, 147 +/- 62, 183 +/- 108, and 173 +/- 38 cm-1, respectively. Tumor volume increased exponentially, with a doubling time of 2 days. Similar results were obtained in nude mice. The model allows detailed repeated observations of angiogenesis and permits quantitative evaluation of tumor growth and angiogenesis in vivo. It is applicable for mechanistic studies as well as therapeutic and pharmacokinetic studies of angiostatic and cytotoxic anti-tumor agents.

Animals↗

PubMed1994

The quinoline-3-carboxamide linomide inhibits angiogenesis in vivo.

Linomide (Roquinimex) has antitumor activity when given in vivo (but not when applied in vitro) that has been attributed to immune host mechanisms. Recent studies, however, suggest that Linomide may also possess antiangiogenic properties. The aim of the present study was to evaluate the antiangiogenic effect of Linomide using an intravital microscopic technique. Syngeneic pancreatic islets were isolated and implanted into the dorsal skinfold chamber of Syrian golden hamsters. This model allows detailed repeated in vivo observations and quantitative analysis of revascularization of pancreatic islet grafts. The neovascularization process of the islets is a highly reproducible phenomenon that is completed within about 2 weeks, resulting in a microvascular network very similar to that of islets in situ. The plasma concentration profile of Linomide following a single oral dose of the compound was determined. The elimination of Linomide was fast, the half-life being 2.6 +/- 0.2 h. Due to the short half-life, the hamsters were given Linomide twice a day. One group of animals (n = 9) was force-fed Linomide (100 mg/kg per day) from the day of implantation throughout the 2-week observation period, and the results were compared with those obtained in a nontreated control group (n = 7). At days 6, 10, and 14 after implantation, the neo-vasculature of the islets was examined. In the control group, 91% +/- 4% (mean +/- SEM) of the islets showed the first signs of angiogenesis at day 6, whereas in the Linomide-treated group the corresponding value was 48% +/- 12%. At days 10 and 14, the "take-rate" in the control group increased to 94% +/- 3% for day 0 and to 94% +/- 4% (n = 6) for day 14, whereas in the treated group the corresponding take-rate was 67% +/- 11% and 72% +/- 12%, respectively. The functional capillary density in the control group at days 6, 10, and 14 was 223 +/- 17,348 +/- 29, and 495 +/- 29 cm-1, respectively, and that in the Linomide treated group was 91 +/- 28, 181 +/- 43, and 229 +/- 47 cm-1, respectively. These results demonstrate that Linomide suppresses the neovascularization of the islet grafts by both delaying the onset of and reducing the percentage of islets displaying angiogenesis as well as by decreasing the rate of proliferation of capillary endothelium of the revascularized islets.

Animals↗

PubMed1993

Estramustine depolymerizes microtubules by binding to tubulin.

To investigate the mechanism of action of the antineoplastic drug estramustine, we compared its effects on human prostate cancer cells with those of vinblastine. At their respective concentrations that result in 50% inhibition of clonogenic growth, both drugs caused an accumulation of cells blocked at mitosis and similar dose- and time-dependent depolymerization of interphase microtubules. Also, colcemid-resistant and colcemid-hypersensitive Chinese hamster ovary cells with tubulin mutations were collaterally cross-resistant or -sensitive to estramustine. Thus, the cytotoxicity of estramustine is due to its microtubule depolymerization properties. This could be caused by interaction with tubulin and/or with microtubule-associated proteins (MAPs). Previous investigations have shown that high concentrations of estramustine phosphate can inhibit microtubule polymerization in vitro by binding to MAPs. However, estramustine phosphate is the clinical prodrug to estramustine, the intracellular active compound. In this study, we investigated the effects of estramustine on the binding of MAPs to taxol-stabilized microtubules in vivo. In contrast to previous reports, no effect of estramustine on the binding of MAPs to microtubules was found. Furthermore, we found that polymerization of purified tubulin could be inhibited by estramustine in vitro. Taken together, these results demonstrate that estramustine causes depolymerization of microtubules by direct interaction with tubulin.

Adenocarcinoma↗

PubMed1993

Antiangiogenic effects of the quinoline-3-carboxamide linomide.

Linomide (N-phenylmethyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxoquinoline-3-carboxa mide) has a reproducible in vivo antitumor effect against a series of both androgen responsive and independent Dunning R-3327 rat prostatic cancers. This antitumor effect of linomide is host mediated. One possible mechanism involving the host is that linomide has antiangiogenic activity. An indication that linomide treatment has antiangiogenic activity is the observation that prostatic cancers from linomide treated rats have more focal necrosis than sized matched tumors from untreated rats. To directly test if linomide has antiangiogenic activity, a newly developed Matrigel based quantitative in vivo angiogenic assay was used. These experiments demonstrated that linomide has dose dependent, antiangiogenic activity in vivo in the rat. Additional studies demonstrated that due to its antiangiogenic activity, linomide treatment of rats bearing prostate cancers resulted in a more than 40% decrease in tumor blood flow. Blood flow to a variety of non-tumor bearing organs was not decreased suggesting that linomide selectively inhibits angiogenesis and does not induce loss of established blood vessels. Using as a model the response of human umbilical vein endothelial cells to linomide treatment in a variety of in vitro assays, linomide was demonstrated to have cytostatic but not cytotoxic effect on human umbilical vein endothelial cells at a medium concentration of > or = 100 micrograms/ml. In addition, both endothelial cell chemotactic migration and invasion are steps in angiogenesis inhibited by linomide treatment.

Adjuvants, Immunologic↗

PubMed1993

Effects of potential aneuploidy inducing agents on microtubule assembly in vitro.

The present study was carried out with the 10 known or suspected spindle poisons of the Commission of the European Communities program to study aneuploidy induction. We have investigated these substances on the assembly of isolated bovine microtubules at 10, 100 and 1000 microM and studied morphology by electron microscopy. The substances could be grouped into two categories, strong and weak inhibitors. Colchicine, vinblastine and thimerosal were strong inhibitors; cadmium chloride, thiabendazole, chloral hydrate, hydroquinone, diazepam and econazole were weak inhibitors, the latter three causing aberrant forms visible on electron microscopy. Pyrimethamine did not inhibit the assembly of microtubules, but produced aberrant forms.

Aneuploidy↗

PubMed1993

Noscapine does not show aneugenic activity in mouse oocytes.

To clarify if noscapine has the ability to induce polyploidy in rodent germ cells in vivo, a cytogenetic study of mouse metaphase II oocytes was conducted after oral treatment with noscapine at the doses of 20, 120 and 400 mg/kg. Plasma concentrations of noscapine were measured by reversed-phase liquid chromatography and UV detection in three satellite groups of mice up to 8 h after administration of these doses. Thus, the relationship of the maximum plasma concentration and the area under the curve (AUC) with that of meiotic progression could be established. Although noscapine was tested at the maximum tolerated dose, no delay of meiotic progression or induction of chromosome malsegregation could be shown as no increase in the frequency of metaphase I-arrested, polyploid or hyperploid oocytes were found. At the highest dose only, noscapine affected the physiology of superovulation as shown by a significant decrease in the mean number of oocytes harvested per female. In view of the large span covered by the doses tested, corresponding to concentrations far above those detected in humans, and the similarity between the pharmacokinetics of noscapine in mouse and humans, it is unlikely that noscapine represents a genetic risk for humans at therapeutic dosages.

Aneuploidy↗

PubMed1992

The antitumor effects of the quinoline-3-carboxamide linomide on Dunning R-3327 rat prostatic cancers.

Linomide (N-phenylmethyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3- carboxamide) is a quinoline 3-carboxamide which previously has been demonstrated to produce immunomodulator and antitumor effects when given in vivo. To test the possible antitumor effects of linomide against prostatic cancers, rats bearing five distinct Dunning R-3327 rat prostatic cancer sublines were treated daily with i.p. injections of linomide. These studies demonstrated that linomide has a reproducible antitumor effect against all of the prostatic cancers tested regardless of their growth rate, degree of morphologic differentiation, metastatic ability, or androgen responsiveness. This antitumor effect is observed only in vivo, not in vitro, and involves a cytotoxic response of the prostatic cancer cells. This cytotoxic response results in the retardation of the growth rate (i.e., increased tumor volume doubling time) of primary prostatic cancers and in metastatic lesions. Linomide's growth retardation is reversible, and thus continuous daily treatment with linomide is required for maximal antitumor response. Pretreatment of rats with linomide before tumor inoculation has no effect in addition to that produced by initiating linomide treatment at the time of tumor inoculation. No enhancement of either natural killer cell number or natural killer cell cytotoxic activity is induced by linomide treatment in the tumor-bearing rats. In addition, depletion of natural killer cell activity via injections of asialo-GM1 antiserum does not prevent the antitumor effects of linomide in vivo. Likewise, the antitumor effects of linomide are also produced in prostatic cancer-bearing athymic nude rats. These results suggest that the requirement for host involvement in the antitumor effects of linomide against rat prostatic cancers may involve both immune and nonimmune host mechanism(s) (e.g., antiangiogenesis).

Adjuvants, Immunologic↗

PubMed1992

Evidence for a non-estrogenic cytostatic effect of estramustine on human prostatic carcinoma cells in vivo.

Estramustine is one of the main metabolites of estramustine phosphate (EstracytR), a drug used in the treatment of advanced prostatic cancer. In the present study the hormone independent human prostatic carcinoma cell line DU 145 implanted subcutaneously in nude mice (NMRI) was used to investigate the mode of action of estramustine in vivo. Metaphase arrest was found in mice treated with estramustine intraperitoneally, 200 and 400 micrograms daily for 2 weeks, 5 days a week. A significant dose dependent decrease in the number of anaphase figures was found. A 7 to 8 fold increase in the number of abnormal metaphases, i.e., highly contracted and unaligned chromosomes, was found. Uptake and retention of 3H-estramustine was found in tumour tissue. No increase in the mitotic index or the number of abnormal metaphases was found in animals treated with polyestradiol phosphate (EstradurinR). This is the first time evidence has been presented demonstrating the anti-mitotic effect of estramustine in vivo.

Animals↗

PubMed1992

Preclinical and clinical perspectives on the use of estramustine as an antimitotic drug.

A variety of cell biological, pharmacological, crystallographic and clinical approaches have indicated that the antimitotic drug estramustine has interesting and unusual properties. Although designed as an alkylating agent, the marked stability of the carbamate linkage to the steroid carrier molecule prevents the formation of alkylating intermediates. The affinity of the parent molecule for microtubule associated proteins and the concomitant antimicrotubule activity have cytotoxic consequences in tumor cells. Both preclinical and clinical studies of estramustine in combination with other antimicrotubule agents have shown that this approach has great potential to achieve therapeutic advantage, especially in disease states such as hormone refractory prostate cancer.

Animals↗

PubMed1992

Genotoxicity of tauromustine, a new water soluble taurine-based nitrosourea. I. Mutagenic and clastogenic activity of tauromustine in vitro.

Tauromustine (TCNU) a new taurine-based nitrosourea in phase III clinical trials against colon cancer, has been tested and compared with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (CCNU) for mutagenic potential in Salmonella typhimurium TA98 and TA100 and, for its ability to cause chromosome aberrations and sister chromatid exchanges (SCE) in human lymphocytes. A dose dependent increase in the number of mutations in S. typhimurium TA100 but not in TA98 was found from 1.6 to 1000 micrograms/plate for both TCNU and CCNU. In addition, in the presence of Aroclor activated liver microsomes, CCNU caused a further increase in the mutation frequency which was not found for TCNU. A dose dependent increase in the chromosome aberration rate in human lymphocytes was induced by both TCNU and CCNU at concentrations ranging from 3.75 to 30 micrograms/ml after 24 h treatment during the last cell cycle. When lymphocytes were treated in G0 both TCNU and CCNU induced a higher frequency of aberrations at 15 and 30 micrograms/ml than during the last cell cycle and, unexpectedly, chromosome-type, i.e. dicentrics appeared. The difference in the frequency of aberrations in these two phases may be related to the different levels of O6-methyl guanine transferase present in resting contra cycling lymphocytes. TCNU at 0.8-8 micrograms/ml also induced a dose dependent increase in the number of SCE in human lymphocytes. Neither the number of chromosomal aberrations nor the number of SCE were affected by the addition of 1000 micrograms/ml taurine to the culture medium.

Antineoplastic Agents↗