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Biomedical subjects

Z Kahán

Publications and source records attributed to Z Kahán.

18 recordsLinked to original sources
PubMed2001

[Multidisciplinary therapy of colorectal cancer].

A multidisciplinary program for the treatment of colorectal cancer is described. The main objective of the authors has been to define uniform up to date guidelines based on recent progress in the treatment of colorectal cancer. Preoperative diagnostic procedures are summarized which advance determination of clinical stage and prognosis. These information essentially determine care. Sequences of surgical methods, preoperative and postoperative radiotherapy and medical treatments are discussed according to tumor stages. Guidelines for surveillance following active treatment and recommendation for the screening of population at high risk for colorectal cancer are presented.

Algorithms↗
PubMed2000

Inhibition of growth of MDA-MB-468 estrogen-independent human breast carcinoma by bombesin/gastrin-releasing peptide antagonists RC-3095 and RC-3940-II.

BACKGROUND: The growth of breast carcinoma is promoted by autocrine growth factors such as the bombesin (BN)-like peptides and epidermal growth factor (EGF). The stimulatory action of BN-like peptides can be blocked by the use of BN/gastrin-releasing peptide (GRP) antagonists. METHODS: The authors investigated the effects of synthetic BN/GRP antagonists RC-3095 and RC-3940-II on tumor growth and the expression of mRNA for EGF receptors and three BN receptor subtypes in MDA-MB-468 human breast carcinoma. Athymic nude mice with xenografts of MDA-MB-468 human breast carcinoma were injected subcutaneously for 6 weeks with RC-3940-II at doses of 20 or 40 microg/day. In another study, the effects of RC-3940-II and RC-3095 were compared. RESULTS: RC-3940-II caused a significant and dose-dependent growth inhibition of MDA-MB-468 tumors in nude mice; therapy with either dose of RC-3940-II significantly (P<0.01) reduced the mean final tumor volume and weight compared with controls. RC-3940-II induced a persistent regression of > 50% of all tumors. One of 3 tumors treated with 20 microg of RC-3940-II and 3 of 5 tumors treated with 40 microg were found to have regressed completely by the end of the study. When RC-3940-II and RC-3095 were compared at the dose of 20 microg/day, both powerfully suppressed growth of MDA-MB-468 tumors, with RC-3940-II causing a complete regression of 2 tumors and RC-3095 a complete regression of 1 tumor. Receptor analyses of untreated MDA-MB-468 tumors revealed an overexpression of EGF receptors and two classes of binding sites for BN/GRP. mRNAs for receptors of GRP, neuromedin B, and BN receptor subtype-3 were detected by reverse transcriptase-polymerase chain reaction. CONCLUSIONS: A virtual arrest of growth or regression of MDA-MB-468 human breast carcinoma after therapy with RC-3940-II and RC-3095 indicates that these BN/GRP antagonists could provide a new treatment modality for breast tumors expressing BN and EGF receptors.

Animals↗
PubMed2000

Administration of a targeted cytotoxic analog of luteinizing hormone-releasing hormone inhibits growth of estrogen-independent MDA-MB-231 human breast cancers in nude mice.

Receptor targeted chemotherapy is less toxic and more effective than conventional chemotherapy. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast cancers. Highly potent cytotoxic radical 2-pyrrolinodoxorubicin (AN-201) was linked to the agonistic analog [D-Lys6]LH-RH to form cytotoxic LH-RH analog AN-207. We evaluated whether AN-207 could be targeted to the hormone-independent MDA-MB-231 human breast cancers. Nude mice bearing MDA-MB-231 tumors were injected i.v. with 250 nmol/kg doses of cytotoxic radical AN-201, cytotoxic LH-RH analog AN-207, the unconjugated mixture of AN-201 and carrier [D-Lys6]LH-RH, [D-Lys6]LH-RH alone and vehicle (control). The growth of MDA-MB-231 tumors in animals given a single dose of AN-207 was inhibited significantly (p = 0.01) for 3 weeks after injection, whereas tumors in all the other groups grew steadily. All cytotoxic compounds produced leukopenia, but the strongest lymphocyte suppression was caused by cytotoxic radical AN-201. Three weeks after treatment, the presence of mRNA for LH-RH receptors was demonstrated by RT-PCR in all the groups and radioreceptor assays demonstrated high-affinity binding sites for LH-RH on tumor cell membranes of control animals and those treated with AN-201, the carrier peptide alone or in combination with AN-201. At this time point binding assays did not reveal the expression of membrane proteins in tumors treated with AN-207, but 60 days after administration of AN-207, high affinity LH-RH binding sites were found again in MDA-MB-231 tumors. These results indicate that cytotoxic LH-RH analog AN-207 could be utilized for receptor targeted chemotherapy of breast cancers expressing receptors for LH-RH.

Animals↗
PubMed2000

Antagonists of growth hormone-releasing hormone arrest the growth of MDA-MB-468 estrogen-independent human breast cancers in nude mice.

Since antagonists of growth hormone-releasing hormone (GH-RH) inhibit proliferation of various tumors, in this study we investigated the effects of GH-RH antagonists MZ-5-156 or JV-1-36 on growth of estrogen-independent MDA-MB-468 human breast cancers xenografted into nude mice. Both GH-RH antagonists administered at a dose of 20 microg/day induced regression of some and growth-arrest of other tumors, while control tumors continued to grow. After 5 weeks of therapy with MZ-5-156 or JV-1-36, final volume and weight of MDA-MB-468 tumors were significantly decreased (all p values < 0.001) and serum IGF-I levels as well as tumor IGF-I mRNA expression were reduced as compared with controls. High affinity binding sites for IGF-I were detected by the ligand binding method. Gene expression of human IGF-I receptors, as measured by the RT-PCR, was not significantly different in control and treated MDA-MB-468 tumors. In cell culture, IGF-I did not stimulate, GH-RH slightly stimulated, while MZ-5-156 and JV-1-36 inhibited proliferation of MDA-MB-468 cells known to possess defective insulin and IGF-I receptor signaling. The expression of mRNA for human GH-RH was found in five of 8 tumors treated with GH-RH antagonists, and in one of the five control tumors. These results suggest that GH-RH antagonists inhibit MDA-MB-468 breast cancers possibly through mechanisms involving interference with locally produced GH-RH.

Animals↗
PubMed1999

Inhibition of growth of MX-1, MCF-7-MIII and MDA-MB-231 human breast cancer xenografts after administration of a targeted cytotoxic analog of somatostatin, AN-238.

Since somatostatin (sst) receptors are expressed in a high percentage of human breast cancers, we studied the effects of a targeted cytotoxic somatostatin analog (AN-238) formed by linking the highly active doxorubicin (DOX) derivative 2-pyrrolino-DOX (AN-201) to octapeptide RC-121 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH(2)) in 3 human breast cancer models. The models included estrogen-independent MDA-MB-231 and MX-1 and estrogen-sensitive MCF-7-MIII tumors. Nude mice bearing xenografts of these cancers were injected i.v. with 250 nmol/kg doses of cytotoxic radical AN-201, cytotoxic analog AN-238 or the unconjugated mixture of AN-201 and sst analog RC-121. Significant inhibition of growth of MDA-MB-231, MX-1 and MCF-7-MIII tumors was observed 1 week after injection of a single dose of cytotoxic analog AN-238. The volume of MDA-MB-231 tumors remained significantly decreased 3 weeks after treatment. The volumes and weights of MCF-7-MIII tumors continued to be significantly reduced 60 days after therapy with AN-238. AN-238 also caused complete regression of MX-1 tumors in 5 of 10 animals, which remained tumor-free 60 days after treatment. In contrast, after treatment with cytotoxic radical AN-201, MDA-MB-231 and MCF-7-MIII tumors grew steadily and the regression of MX-1 tumors was only transitory in most animals. Toxicity of AN-201 was much greater than that of AN-238, as measured by animal deaths, loss of body weight and leukopenia. High-affinity sst receptors and mRNA for both sst(2) and sst(5) subtypes were found in all 3 tumor lines. Expression of sst receptors was not significantly affected by treatment with AN-238. Our results indicate that the cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast cancers expressing sst receptor subtypes 2 and 5.

Animals↗
PubMed1999

Complete regression of MX-1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone-releasing hormone, AN-207.

BACKGROUND: Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast carcinomas. A highly potent cytotoxic agent, 2-pyrrolinodoxorubicin (AN-201), was linked to the agonist [D-Lys6]LH-RH to form a cytotoxic LH-RH analog, AN-207, that can be targeted to LH-RH receptors on breast carcinomas. METHODS: Nude mice bearing MX-1 hormone-independent, doxorubicin-resistant human breast carcinomas were injected intravenously with vehicle (control), 250 nmol/kg doses of AN-201, AN-207, or an unconjugated mixture of AN-201 and [D-Lys6]LH-RH. Tumor growth and changes in hematologic parameters were evaluated. Receptors for LH-RH were investigated by radioreceptor assays, and the expression of their mRNA was determined by reverse transcriptase-polymerase chain reaction. RESULTS: AN-207 caused complete regression of MX-1 tumors in all 10 animals, and they were still tumor free 60 days after treatment. In contrast, after therapy with AN-201 or the mixture of AN-201 and [D-Lys6]LH-RH, the regression of most MX-1 tumors was only transitory. AN-201 caused the death of 1 of the 10 animals and significantly greater leukopenia than AN-207, which produced no toxic deaths. Radioreceptor assays revealed high affinity binding sites for LH-RH on tumor cell membranes. The expression of mRNA for LH-RH receptors also was found in tumors. CONCLUSIONS: The results of this study indicate that powerful, targeted cytotoxic LH-RH analogs such as AN-207 could be considered for the treatment of human breast carcinomas that possesses receptors for LH-RH.

Animals↗
PubMed1999

Expression of growth hormone-releasing hormone (GHRH) messenger ribonucleic acid and the presence of biologically active GHRH in human breast, endometrial, and ovarian cancers.

GHRH is produced in a variety of extrahypothalamic tissues, including some neoplasms. We have previously reported that GHRH antagonists can inhibit the growth of various human cancers xenografted into nude mice. These observations suggest that locally produced GHRH might directly affect tumor cell proliferation. To investigate this possibility, we have examined the local production of GHRH in human endometrial, ovarian, and breast cancers obtained after surgery or grown in nude mice as xenografts. We have also examined whether the GHRH produced in these tumors is biologically active. RT-PCR and Southern blotting showed expression of messenger ribonucleic acid for GHRH in 17 of 22 endometrial and 17 of 22 ovarian cancer specimens and in all of the human endometrial, ovarian, and breast cancer xenografts studied. Acid extracts of endometrial cancer specimens and breast cancer xenografts that expressed the GHRH gene contained immunoreactive GHRH peptide, as assessed by RIA for GHRH. The level of immunoreactive GHRH detected was equivalent to 2.7-6.4 ng GHRH-(1-29)/g tissue. Purified extract from one of these tumor samples induced a powerful stimulation of GH release from rat pituitary cells. The presence of biologically and immunologically active GHRH and messenger ribonucleic acid for GHRH in human breast, endometrial, and ovarian cancers supports the hypothesis that locally produced GHRH may play a role in the proliferation of these tumors.

Adult↗
PubMed1998

Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin.

To create cytotoxic hybrid analogs of somatostatin (SST), octapeptides RC-160 (D-Phe-Cys-Tyr-D-Trp- Lys-Val-Cys-Trp-NH2) and RC-121 (D-Phe-Cys-Tyr-D-Trp- Lys-Val-Cys-Thr-NH2) were linked to doxorubicin (DOX) or its superactive derivative, 2-pyrrolino-DOX (AN-201). The conjugation was performed by coupling N-9-fluorenylmethoxycarbonyl (N-Fmoc)-DOX-14-O-hemiglutarate or 2-pyrrolino-DOX-14-O-hemiglutarate to the amino terminus of [Lys(Fmoc)5]RC-160 yielding AN-163 and AN-258, respectively, after deprotection. The respective cytotoxic conjugates of RC-121 (AN-162 and AN-238) were prepared similarly. In vitro tests on human cancer cell lines-MKN-45 gastric cancer, MDA-MB-231 breast cancer, PC-3 prostate cancer, and MIA PaCa-2 pancreatic cancer-demonstrated that the antiproliferative activity of the cytotoxic radicals in these conjugates was virtually retained. In H-345 human small cell lung carcinoma cell line, conjugates of RC-121 preserved the cytotoxic activity of their radicals, but the hybrids with RC-160 showed approximately 10 times lower activity. The ability of the carriers and the hybrids to inhibit the binding of 125I-labeled RC-160 to receptors for SST on rat pituitary membrane preparation was also determined. The cytotoxic conjugates inhibited 50% of the specific binding of the radioligand in the nanomolar concentration range (IC50 < 80 nM). When SST-like activities of AN-238 and its carrier, RC-121, were compared in the rat pituitary superfusion system, both compounds were found to suppress a stimulated growth hormone release at nanomolar concentrations. Preliminary studies in animal models of breast and prostate cancers showed that AN-238 is less toxic than AN-201 and more potent in inhibiting tumor growth. These highly active cytotoxic analogs of SST have been designed as targeted antitumor agents for the treatment of various cancers expressing receptors for SST octapeptides.

Animals↗
PubMed1997

Recurrent phyllodes tumor in a man.

The case of a 35-year-old man with a borderline-type cystosarcoma phyllodes is presented. Four years after the primary excision of the tumor, wide excision of a local recurrence and postoperative radiotherapy were performed. No repeated relapse was observed during a 5-year follow-up. Neither significant endocrine changes nor genetic alteration could be proven. However, a slightly increased SHBG concentration was detected, resulting in a decreased biologically available androgen level reduced testosterone/SHBG index. This phenomenon might be a consequence of the chronic liver disease of the patient due to his type II diabetes mellitus and alcohol abuse. In addition to the conventional histopathological examinations, immunohistochemical and electron-microscopic investigations were carried out on tissue sections, and the steroid receptors, EGF receptors and EGF-like activity of the tumor were also studied.

Adult↗
PubMed1996

[Current questions about estrogen receptor determination and hormone dependence (does estrogen receptor positivity equal estrogen dependence?)].

Exaggerated expectations were raised by estrogen and progesterone receptor determinations introduced in the 1970s for the estimation of hormone dependence. However only two thirds of estrogen and/or progesterone receptor positive cases respond to hormonal therapy. Radioligand binding immuno-assays, and immunohistochemical determinations are wide-spread, however not informative enough. The former two performed on tumor homogenate can not take into account the tissue composition, and heterogeneity of the tumor, and fail to detect receptors of the ligand-saturated forms, while the immunological methods do not give any functional information. There is increased evidence on the existence of dysfunctional estrogen receptor variants. One presents estrogen receptor negative progesterone receptor positive phenotype unable to bind its ligand but constitutively activates its specific DNA-sequence. The other most prevalent in estrogen receptor positive progesterone receptor negative tumors is a mutant "infertile" variant able to hamper normal function of the wild type estrogen receptor by heterodimerization. In order to better utilize estrogen, and progesterone receptor data, propositions are made as following: estrogen receptors from occasionally simultaneously performed biochemical and immunohistochemical determinations should be evaluated in context with other characteristics of the tumor; the detection of mutated defective estrogen receptors may suggest hormone resistance. The correct estimation of the prevalence or lack of hormone dependence is mandatory when systemic treatment-especially in the adjuvant setting is becoming more and more individualized in breast cancer.

Adult↗
PubMed1993

Epidermal growth factor-like activity and epidermal growth factor-receptors in human primary breast cancer.

Ligands binding to epidermal growth factor-receptors (EGF-Rs) as epidermal growth factor-like activity (EGF-like activity), along with EGF-R levels, were determined from human primary breast cancer samples. Receptor analysis revealed a single class of high affinity binding sites. Ng/mg protein EGF-like activity quantities were measured in cytosols, and were inversely correlated with EGF-R contents (p < 0.01), estimated by two-point assays.

Breast Neoplasms↗
PubMed1992

Low-dose aminoglutethimide therapy without glucocorticoid administration. Clinical and hormonal findings.

Eleven postmenopausal patients with advanced breast cancer were assessed for their response and endocrine changes to low-dose aminoglutethimide (250 mg twice a day) therapy without steroid administration. In 7 cases an objective response was registered; 1 patient had a stabilization of the disease lasting for 9 months. Significant falls in plasma estrogen and rises in plasma androgen levels were observed, while those of cortisol and ACTH remained essentially unchanged. No serious side effects occurred.

Aged↗
PubMed1992

Hormone therapy in breast cancer.

Means and the currently accepted principles of hormone therapy of breast cancer have been summarized on the basis of data from references. Fields of application and adverse effects of anti-oestrogens, aromatase inhibitors, gestagens, gonadotrophin-releasing, and androgenic hormones have been analysed. Drugs with various mechanisms of action and available in Hungary have been discussed.

Androgens↗
PubMed1990

[Therapeutic use of a gonadotropin releasing hormone analogue in breast cancer].

Superagonistic analogues of Gn-RH given chronically produce a paradoxic inhibition of pituitary gonadotropin secretion and consequently decrease the peripheric hormones estradiol and progesterone to a postmenopausal level. For curative purposes buserelin (SuprefactR, Hoechst) treatment has been performed by the authors in two cases of breast cancer. The patients--one with NED (no evidence of disease) and the other with pulmonary and osseal metastases--in addition to low hormonal levels developed amenorrhoea. A group of climacteric complaints were observed without any toxic side effects, however. The treatment of premenopausal women suffering from breast cancer with chronic administration of Gn-RH analogues may constitute a valuable alternative to surgical oophorectomy.

Breast Neoplasms↗
PubMed1987

Mucosal blood flow changes in the human stomach measured by the 99mTc-4-methylaminophenazone clearance technique.

The effect of gastric secretory inhibitors, vasoactive agents and gastrointestinal peptide hormones were investigated on gastric mucosal blood flow (MBF) and HCl secretion in 197 subjects. Changes in MBF were estimated by a new clearance substance, 99mTc-4-methyl-aminophenazone originally described by the authors. The procedure seemed to be suitable for characterizing changes in MBF without any toxic side effect or considerable radioactive loading of the patient or its surroundings. The studies were performed after a secretory steady state had been achieved by continuous pentagastrin infusion. Some experiments were done in the fasting stomach instilled with 0.160 N HCl. Secretory inhibition following atropine, pirenzepine, ranitidine and somatostatin was a primary effect of these substances, the observed MBF decrease being a secondary one. In contrast, vasopressin caused a fall in mucosal blood supply through vasoconstriction, the concomitant secretory inhibition being a secondary phenomenon. Certain doses of dopamine and terbutaline increased MBF without influencing HCl secretion. Glucagon in the dose used did not influence either mucosal blood flow or acid secretion. Synthetic secretin in the fasting stomach increased MBF without affecting HCl production; during pentagastrin stimulation it inhibited acid production while MBF remained unchanged. Cholecystokinin-octapeptide proved to be a direct vasodilating agent with a slight acid output increasing effect. Divergent effects of some drugs on mucosal blood flow and HCl production may be important in the pathology of hypoxic ulcerative damage and in the reparative processes of gastric ulceration. The 99mTc-4-methyl-aminophenazone clearance technique proved to be a reliable method for screening of drugs possessing vasoactive or secretion influencing properties.

Aminopyrine↗
PubMed1986

Changes in gastric mucosal blood flow in patients with duodenal ulcer following proximal selective vagotomy (PSV).

Pentagastrin-stimulated mucosal blood flow and acid secretion were studied in duodenal ulcer patients by means of the 99mTc-4-methylaminophenazone clearance method in the active and inactive phases of the disease, and before and after proximal selective vagotomy. The results suggest that the mucosal blood flow--acid secretion ratio in the patients differs from that found in normosecretory subjects. In duodenal ulcer patients in the inactive phase, the secretory capacity of the gastric mucosa was found to be significantly elevated as compared with the mucosal blood flow. In the active phase of the disease the mucosal blood flow increased in parallel with acid secretion. Following proximal selective vagotomy the normal blood flow-secretion ratio was restored. Comparison of the pre- and postoperative gastric mucosal blood flow and secretion values via the 99mTc-methylaminophenazone clearance technique proved useful for the evaluation of the effectiveness of vagotomy.

Adult↗