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Attila Nagy

Publications and source records attributed to Attila Nagy.

At least 55 records · Page 3Linked to original sources
PubMed2003

Two types of neuron are found within the PPT, a small percentage of which project to both the LM-SG and SC.

The pedunculopontine tegmental nucleus (PPT) projects its cholinergic fibers to both the lateralis medialis-suprageniculate nucleus (LM-Sg) and the superior colliculus (SC). For the purpose of verification of whether a single neuron in the PPT projects to both the LM-Sg and the SC, we injected dextran tetramethylrhodamine (DR) into the LM-Sg and dextran fluorescein (DF) into the ipsilateral SC. The DR-positive neurons labeled retrogradely in the PPT are small (mean: 27.13+/-1.22 micro m) and distributed in the rostral two-thirds of this nucleus, whereas the DF-positive neurons are small (mean: 27.54+/-1.16 micro m) or medium-sized (mean: 40.18+/-1.43 micro m), and are located throughout the PPT. Thirty-five percent of all labeled neurons are double-labeled and small. The present study indicates that the PPT projection to the LM-Sg in part involves neurons bifurcating to the SC.

Acetylcholine↗
PubMed2003

Preclinical evaluation of therapeutic effects of targeted cytotoxic analogs of somatostatin and bombesin on human gastric carcinomas.

BACKGROUND: New modalities are necessary for the treatment of patients with unresectable gastric carcinoma. The authors investigated whether receptors for somatostatin and bombesin were present in human gastric carcinoma lines and tested the antitumor effects of cytotoxic somatostatin analog AN-238 and cytotoxic bombesin conjugate AN-215. METHODS: Nude mice bearing AGS, Hs 746T, and NCI-N87 human gastric carcinomas were treated with AN-238, AN-215, or their cytotoxic moiety 2-pyrrolinodoxorubicin (AN-201). Tumor growth reduction and tumor doubling times were calculated, and histologic characteristics of cell proliferation and apoptosis were examined. The expression of mRNA for somatostatin and bombesin receptors in tumors was investigated by reverse transcriptase-polymerase chain reaction. Subtypes 2 and 5 of somatostatin receptor proteins (sst2 and sst5, respectively) were analyzed using immunohistochemistry and immunoblotting. Binding assays were performed with radiolabeled somatostatin and bombesin analogs. RESULTS: Cytotoxic bombesin analog AN-215 powerfully inhibited the growth of AGS carcinomas that expressed high-affinity subtype 1 bombesin receptors. All three carcinomas expressed high-affinity sst2 and sst5 receptors. Cytotoxic somatostatin analog AN-238 exerted a strong inhibitory effect on NCI-N87 and Hs 746T carcinomas, which exhibited high concentrations of somatostatin receptors, but had a weaker effect on AGS tumors, which expressed the lowest receptor levels. AN-201 had only nonsignificant effects. CONCLUSIONS: Experimental human gastric carcinomas that expressed high-affinity subtype 1 bombesin receptors were inhibited by cytotoxic bombesin analog AN-215, and tumors with high concentrations of sst2 or sst5 somatostatin receptors were suppressed by cytotoxic somatostatin analog AN-238. These findings suggest that this class of targeted compounds should be considered for the therapy of patients with advanced gastric carcinoma.

Analysis of Variance↗
PubMed2003

Preclinical evaluation of targeted cytotoxic luteinizing hormone-releasing hormone analogue AN-152 in androgen-sensitive and insensitive prostate cancers.

PURPOSE AND EXPERIMENTAL DESIGN: To improve conventional chemotherapy, we developed cytotoxic analogues of luteinizing hormone-releasing hormone (LH-RH), which can be targeted to prostate cancers expressing LH-RH receptors. In view of pending clinical trials on cytotoxic LH-RH analogue AN-152, containing doxorubicin (DOX) linked to [D-Lys(6])-LH-RH, we investigated the effects of AN-152 on tumor growth of s.c. implanted androgen-sensitive LNCaP and MDA-PCa-2b prostate cancers, as well as androgen-independent C4-2 prostate cancers xenografted into the tibiae of nude mice. In the C4-2 study, serum prostate-specific antigen (PSA) levels were also measured. LH-RH receptors were analyzed by reverse transcription-PCR and ligand competition assay. We also evaluated whether AN-152 can affect mRNA expression of human epidermal growth factor receptor and HER-2 and -3 oncogenes RESULTS: After 32 days of treatment with AN-152, the growth of LNCaP cancers in castrated nude mice was strongly inhibited by 83% versus intact controls (P < 0.01) and 62% versus castrated controls (P < 0.05). In animals bearing MDA-PCa-2b prostate cancers, therapy with AN-152 for 25 days resulted in a 69% inhibition of tumor growth (P < 0.01 versus controls) and was more effective (P < 0.05) than equimolar doses of DOX or microcapsules of LH-RH agonist Decapeptyl. In nude mice bearing intraosseous C4-2 prostate cancers, treatment with AN-152 decreased serum PSA levels (P < 0.01) to 10.3 +/- 3.4 ng/ml from 24.8 +/- 4 ng/ml in controls, whereas DOX had no effect on PSA. The inhibitory effects of AN-152 on C4-2 tumors was accompanied by an increase in apoptosis and a decrease in tumor proliferation. Binding sites for LH-RH and the expression of mRNA for LH-RH receptors were found on s.c. C4-2 and MDA-PCa-2b tumors. The inhibition of MDA-PCa-2b tumors by AN-152 was associated with a significant decrease in mRNA expression for epidermal growth factor receptor, HER-2, and 3. CONCLUSIONS: Our findings suggest that cytotoxic analogue AN-152 could be considered for therapeutic trials in patients with advanced prostate carcinoma.

Androgens↗
PubMed2003

Targeted doxorubicin-containing luteinizing hormone-releasing hormone analogue AN-152 inhibits the growth of doxorubicin-resistant MX-1 human breast cancers.

PURPOSE: The receptors for luteinizing hormone-releasing hormone receptor (LHRH-R) are found in >50% of human breast cancers. Doxorubicin (DOX) was linked to [D-Lys(6)]LHRH to form a cytotoxic conjugate, AN-152, which can be targeted to tumor cells expressing LHRH-R. We evaluated the effects of AN-152 on the estrogen-independent, DOX-resistant human mammary carcinoma line MX-1, xenografted into nude mice. EXPERIMENTAL DESIGN: Nude mice bearing MX-1 tumors were administered five i.v. injections of AN-152 or DOX at doses equivalent to 3 mg/kg DOX. Tumor growth was followed, and changes in the expression of LHRH-R on tumors were evaluated by radioreceptor assays, reverse transcription-PCR, and Western blotting. The effects of AN-152 on the expression of human epidermal growth factor receptor (HER)-2 were investigated. Because LHRH-R are coupled to various G proteins, which are involved in mitogenic signaling, we determined the outcome of treatment with AN-152 on the levels of mRNA for different G proteins. RESULTS: Treatment with AN-152 significantly (P < 0.05) decreased the final tumor volume to 978.56 +/- 176.85 mm(3), compared with the control tumors, which measured 2837.38 +/- 515.38 mm(3). Tumor doubling time was likewise significantly (P < 0.05) extended by AN-152 to 12.01 +/- 1.99 days from 6.45 +/- 0.36 days for the controls. Therapy with AN-152, but not with DOX, resulted in a significant decrease of LHRH-R levels on MX-1 tumors. The expression of mRNAs for HER-2, HER-3, Galpha(i2), and Galpha(11) and the levels of HER-2 and HER-3 proteins were also significantly reduced by AN-152. CONCLUSIONS: Cytotoxic LHRH analogue AN-152 could be considered for targeted chemotherapy of DOX-resistant breast cancers expressing LHRH-R.

Animals↗
PubMed2003

Spatial and temporal visual properties of single neurons in the feline anterior ectosylvian visual area.

The spatial and temporal visual sensitivity to drifting sinusoidal gratings was studied in 75 neurons of the feline anterior ectosylvian visual area (AEV). Extracellular single-unit recordings were performed in halothane-anesthetized (0.6%), immobilized, artificially ventilated cats. Most cells were strongly sensitive to the direction of drifting gratings. The mean value of the direction tuning widths was approximately 90 deg. Most of the cells (69 of the 75 cases) displayed rather narrowly tuned band-pass characteristics in the low spatial frequency range, with a mean optimal spatial frequency of 0.2 cycles/degree (c/deg). The mean spatial bandwidth was 1.4 octaves. The remainder of the units was low-pass tuned. A majority of the units responded optimally to high temporal frequencies (mean 6.3 Hz), although some cells did exhibit preferences for every examined temporal frequency between 0.6 Hz and 10.8 Hz. The temporal frequency-tuning functions mostly revealed a band-pass character with a mean temporal bandwidth of 1.1 octaves. Our results demonstrate that the neurons along the anterior ectosylvian sulcus display particular spatial and temporal characteristics. The AEV neurons, with their preference for low spatial frequencies and with their fine spatial and temporal tuning properties, seem to be candidates for special tasks in motion perception.

Animals↗
PubMed2003

Absence of binding of targeted analogs of somatostatin carrying cytotoxic radicals or radionuclides to growth hormone secretagogue receptors on human myocardium.

Various peripheral human tissues express receptors for growth hormone secretagogue (GHS), the highest density being in the myocardium. It was also reported that some octapeptide analogs of somatostatin (SRIH) can displace radiolabeled Tyr-Ala-hexarelin from GHS receptors on the human pituitary and heart. Thus, it is possible that radionuclide analogs of SRIH such as OctreoScan and recently developed cytotoxic SRIH analogs containing doxorubicin (DOX) intended for targeted tumor therapy, could bind to these GHS receptors, compromising the safety of compounds of this type. Therefore, we determined the binding of OctreoScan and two cytotoxic SRIH analogs consisting of octapeptide carrier RC-121 and DOX (AN-162) or 2-pyrrolino-DOX (AN-238) to human myocardium specimens. None of these compounds displayed specific binding to the human heart indicating that the clinical use of SRIH analogs linked to anthracyclines or radionuclides should not be associated with increased cardiac side effects.

2-Hydroxyphenethylamine↗
PubMed2003

New approaches to treatment of various cancers based on cytotoxic analogs of LHRH, somatostatin and bombesin.

The development of targeted cytotoxic analogs of hypothalamic peptides for the therapy of various cancers is reviewed and various oncological studies on experimental tumors are summarized. Novel therapeutic modalities for breast, prostate and ovarian cancer consist of the use of targeted cytotoxic analogs of LH-RH containing doxorubicin (DOX) or 2-pyrrolino-DOX. The same radicals have been incorporated into cytotoxic analogs of somatostatin which can be also targeted to receptors for this peptide in prostatic, mammary, ovarian, renal and lung cancers, brain tumors and their metastases. A targeted cytotoxic analog of bombesin containing 2-pyrrolino-DOX has also been synthesized and successfully tried in experimental models of prostate cancer, small cell lung carcinoma and brain tumors. The development of these new classes of peptide analogs should lead to a more effective treatment for various cancers.

Animals↗
PubMed2003

[Reconstructive surgery of the upper limbs in the rehabilitation of tetraplegia--case report].

As part of the rehabilitation of tetraplegic patients, movement improving operations have been carried out for more than 30 years. The scant results of the early 70's caused such a standstill and division among professionals, that operations on the upper limbs on tetraplegic patients became questionable. The authors started operating upper limb reconstructions on tetraplegia patients for achieving a basic hand function i.e. key pinch, grasping etc. in 2001. Three cases are quoted and one of them, operated ten months ago is described in details. The postoperative treatment of the other two patients has not finished yet. In 1998, a twenty-three years old girl had her fifth and sixth cervical vertebra broken in a car accident. The rugged break of the fifth vertebral body damaged the spinal chord. After the accident all four limbs became ataxic and a complete numbness occurred distally from the thoracic level of the chest. The patient went through a CV corpectomia, a corpus complementation, a CIV-V dissectomia and a CIV-VII ventrofixation. After the operation the movements of the upper limbs improved but those of the lower limbs did not. Her general condition stabilised after the treatments at the intensive care and the laryngological, the urological and the plastic surgery as well as the complex therapy at the rehabilitation department. She moved around in a wheelchair. After a para-coordinational treatment she was able to lift up small objects, but because of her paralysed bending and stretching finger muscles she was not able to hold heavier objects with her hands. In March 2002 a grip improving operation was carried on her dominant right hand. Twelve weeks after the operation she could lift up a weight of 2 kg and she was able to key pinch and grip with force.

Adult↗
PubMed2003

Visual receptive field properties of neurons in the caudate nucleus.

Visual single-unit activity was recorded in the caudate nucleus of halothane-anaesthetized, immobilized, artificially respirated cats. Visually sensitive neurons were found in the dorsolateral part of the caudate body. A majority of the units responded optimally to small spot-like stimuli moving with velocities between 30 and 120 degrees /s. The receptive field of these units is large: it covers a major part of both the contra- and ipsilateral visual hemifields. No signs of retinotopy were observed. Most of the neurons display directional selectivity and are narrowly tuned to the direction of the moving stimulus. These physiological properties are consistent with recent morphological results that reveal multiple connections of the caudate nucleus with the superior colliculus through tecto-extrageniculo-thalamic pathways in the mammalian brain.

Anesthesia↗
PubMed2003

Effective treatment of H838 human non-small cell lung carcinoma with a targeted cytotoxic somatostatin analog, AN-238.

The accumulation of radioactive somatostatin analog [111In]pentetreotide in non-small cell lung cancer (non-SCLC) during scintigraphy of patients provides a rationale for investigating the efficacy of somatostatin receptor-based chemotherapy in non-SCLC. Consequently, in this study, we evaluated the antitumor effects of cytotoxic somatostatin analog AN-238 on H838 human non-SCLC xenografted into nude mice in comparison with its cytotoxic radical, 2-pyrrolinodoxorubicin (AN-201). The expression of messenger RNA (mRNA) for human somatostatin receptor subtypes 2 (hsst2) and 5 (hsst5) in H838 cells, and tumors was also investigated using reverse-transcription polymerase chain reaction (RT-PCR). Somatostatin receptors on H838 tumors were characterized by ligand competition assay using radiolabeled somatostatin analog, RC-160. Three i.v. injections of AN-238 at 150 nmol/kg, given on days 1, 7 and 21, resulted in a significant (p<0.05) tumor growth inhibition, the final tumor volume being 60% smaller than in the controls. The tumor doubling time was also extended significantly (p<0.05) from 9.65+/-0.56 days in the controls to 17.52+/-3.3 days. Only one of 8 mice died due to toxicity. In contrast, cytotoxic radical AN-201 was ineffective and more toxic, killing 2 of 7 animals. mRNA for hsst2 was found in H838 xenografts, but not in H838 cells from which the xenografts originated. Interestingly, H838 cells grown in a special, serum-free medium did express mRNA for hsst2. mRNA for hsst5 was not found in any samples tested. Binding studies demonstrated the presence of high affinity (K(d) = 7.3+/-1.2 nM) binding sites for RC-160 with a mean maximal binding capacity (B(max)) of 953.3+/-45.3 fmol/mg protein. AN-238 at 3.14+/-0.93 nM concentration displaced 50% of radiolabeled RC-160 binding to somatostatin receptors in H838 tumors. Our results indicate that patients with inoperable non-SCLC may benefit from chemotherapy targeted to somatostatin receptors based on AN-238.

Animals↗
PubMed2002

Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study.

BACKGROUND: Edrecolomab is a murine monoclonal antibody to the cell-surface glycoprotein 17-1A, which is expressed on epithelial tissues and on various carcinomas. Preliminary data suggested that it might be of use in the adjuvant treatment of patients with resected stage III colon cancer. We did a randomised trial in 27 countries to determine the effect of adding edrecolomab to the combination of fluorouracil and folinic acid in these patients. METHODS: After surgery, 2761 patients were randomly assigned edrecolomab plus fluorouracil-folinic acid (combination therapy [n=912]); fluorouracil-folinic acid alone (chemotherapy [n=927]); or edrecolomab alone (edrecolomab monotherapy [n=922]). Patients were assessed for survival and disease recurrence after surgery. The primary endpoint tested the hypothesis that combination therapy improved overall survival relative to chemotherapy. The key secondary endpoint was to test whether edrecolomab monotherapy was non-inferior to chemotherapy in terms of disease-free survival. Analysis was by intention to treat. FINDINGS: Median follow-up time was 26 months (IQR 20-36). 3-year overall survival on combination therapy was no different from that on chemotherapy (74.7% vs 76.1%, hazard ratio 0.94 [95% CI 0.76-1.15], p=0.53). Disease-free survival was significantly lower on edrecolomab monotherapy than on chemotherapy (53.0% vs 65.5%, 0.62 [0.53-0.73], p<0.0001). Hypersensitivity reactions occurred in 452 (25%) patients receiving edrecolomab, causing treatment discontinuation in 71 (4%). The addition of edrecolomab to chemotherapy did not increase neutropenia, diarrhoea, or mucositis. INTERPRETATION: The addition of edrecolomab to fluorouracil and folinic acid in the adjuvant treatment of resected stage III colon cancer does not improve overall or disease-free survival, and edrecolomab monotherapy is associated with significantly shorter overall and disease-free survival than fluorouracil and folinic acid and is therefore an inferior treatment option. Edrecolomab is well tolerated and its addition to fluorouracil and folinic acid does not increase the toxicity of chemotherapy.

Aged↗
PubMed2002

[Does the TT virus affect T-cell subgroups in patients undergoing hemodialysis?].

BACKGROUND: Recently many publications have appeared about the new DNA virus, called transfusion transmitted virus (TT virus), first described in 1997. These are mainly about the virus epidemiology, gene sequences and the distribution of different genotypes. In spite of the fact that the prevalence of this type of infection can reach 40 percent rate in polytransfused patients, such as in hemodialysis patients, the real pathogenetic effect of the virus has not yet been known. AIMS: The aim of the authors was to examine the activation and distribution of mononuclear cells in peripheral blood and to analyse the possible changes in Th1/Th2 immune regulatory mechanism through the soluble and intracellular cytokine profile beside the biochemical parameters of hepatic lesions in TT virus positive (n = 32) and negative (n = 17) hemodialysed patients. Healthy blood donors were the control group (n = 20). METHOD: Semi-nested PCR was used to detect the DNA of TT virus. For the surface antigen (CD3, CD4, CD8, CD19, CD56, CD3/HLA-DR, CD3/CD69) and intracellular cytokine analysis the authors applied flow cytometric method. RESULTS: The authors did not find any differences in the liver specific biochemical parameters between TT virus positive and negative hemodialysed and the healthy control group. The number of total T, T helper and total B cells were decreased. The percentage of CD8+, CD3+/HLA-DR+, CD3+/CD69+ and CD56+ cells were increased significantly in both hemodialysed population independently the presence or absence of TT virus. The soluble and intracellular cytokines showed significant growth of the Th1/Th2 cells ratio in hemodialysed patients, which has not been modified by the virus. CONCLUSIONS: From these results the authors assume that the TT virus does not cause any significant changes in the immune regulation, although it could play some role in the pathogenesis of hepatitis by local reaction.

Adult↗
PubMed2002

Inhibition of in vivo proliferation of MDA-PCa-2b human prostate cancer by a targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207.

The efficacy of therapy with targeted cytotoxic luteinizing hormone-releasing hormone (LHRH) analog AN-207 consisting of superactive doxorubicin derivative AN-201 linked to carrier [D-Lys(6)]LH-RH was evaluated in vivo in nude mice bearing xenografts of MDA-PCa-2b prostate cancer line. AN-207 was administered intravenously (i.v.) at 200 nmol/kg on day 1 and at 150 nmol/kg on day 14. After 4 weeks of treatment with AN-207, tumor growth was inhibited as shown by a 63% (P<0.01) decrease in tumor volume and a 55% (P<0.05) reduction in tumor weight, compared with controls. None of the animals died after administration of AN-207 at the total dose of 350 nmol/kg, and at the end of the experiment the body weights of mice given AN-207 did not differ significantly from controls. A single injection of cytotoxic radical AN-201 at 200 nmol/kg resulted in 43% mortality. In the surviving mice, AN-201 caused a 50% inhibition in tumor volume and a 27% reduction in tumor weight, which were non-significant, as compared to the controls. After 4 weeks, serum prostate-specific antigen concentrations in mice treated with AN-207 were 65% lower than those in controls (P<0.05), while in animals given AN-201 the reduction in serum prostate-specific antigen was only 40% (NS). The expression of mRNA for LHRH receptors was detected by reverse transcriptase polymerase chain reaction (RT-PCR) in MDA-PCa-2b tumors. The present study indicates that chemotherapy targeted to LHRH receptors on tumors inhibits growth of MDA-PCa-2B prostate cancers representative of human carcinoma disseminated to the bone and progressing despite androgen withdrawal.

Animals↗
PubMed2002

Targeted cytotoxic somatostatin analogue AN-238 inhibits somatostatin receptor-positive experimental colon cancers independently of their p53 status.

The resistance of advanced colorectal cancers to therapy is often related to mutations in the p53 tumor suppressor gene. Because somatostatin (SRIF) receptors (ssts) are present in colorectal carcinomas, the treatment with targeted cytotoxic SRIF analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to octapeptide SRIF carrier RC-121, may overcome this resistance by producing a higher concentration of the cytotoxic agent in the tumors. Four colon cancer cell lines, HCT-116 and LoVo expressing wild-type p53, and HCT-15 and HT-29 with mutated p53, were investigated. HCT-116, HCT-15, and HT-29, but not LoVo possess functional ssts. We analyzed changes in p53, p21, and proliferating cell nuclear antigen (PCNA) concentrations in these cells in vitro by immunoblotting after exposure to AN-238, its radical AN-201, or doxorubicin (DOX). Equitoxic doses of AN-238, AN-201, or DOX affected p53, p21, and PCNA differently. Analysis of the p21:p53 ratios revealed that DOX increased p53 levels, but most of p53 was mutated and inactive, whereas AN-238 produced smaller changes in p53 concentrations but enhanced its activity. In HCT-15 cells, PCNA:p21 ratios, which are indicators of proliferation and repair processes, remained unchanged after exposure to AN-238 but were increased by DOX. In vivo studies in nude mice demonstrated that AN-238, AN-201, and DOX were equally effective on HCT-116 tumors that express wild-type p53. However, AN-238 also inhibited the growth of HCT-15 and HT-29 cancers that express mutant p53, whereas AN-201 and DOX showed no effect. None of the compounds could suppress the proliferation of LoVo tumors that lack functional ssts. In conclusion, cytotoxic SRIF analogue AN-238 inhibits the growth of experimental colon cancers that express ssts, regardless of their p53 status.

Animals↗
PubMed2002

Early nasojejunal feeding in acute pancreatitis is associated with a lower complication rate.

OBJECTIVE: We investigated the effect of early jejunal feeding on septic complications and mortality rate in patients with acute pancreatitis in a two-phase, prospective, controlled study. METHODS: In the first, randomized phase of the study, conventional parenteral nutrition was compared with early (within 24-72 h after the onset of symptoms) enteral nutrition. Of 89 patients admitted with acute pancreatitis, 48 patients were randomized into a parenteral group (Rindex 10, Infusamin S, Intralipid 10%; 30 kcal/kg) and 41 patients into an enteral group (jejunal tube feeding; Survimed OPD; 30 kcal/kg). RESULTS: The rate of septic complications (infected pancreatic necrosis, abscess) was lower in the enteral group (P = 0.08, chi(2) test). In the second phase of the study, early jejunal feeding was combined with prophylactic imipenem (Tienam, 500 mg intravenously twice each day) when necrosis of the pancreas was detected by abdominal computed tomography. When the outcomes of 92 patients in the third group were compared with those of patients in the parenteral group, the rate of septic complications decreased significantly (P = 0.03). Multiple organ failure (P = 0.14) and mortality (P = 0.13) tended to decrease. CONCLUSIONS: We believe that the combination of early enteral nutrition and selective, adequate antibiotic prophylaxis may prevent multiple organ failure in patients with acute pancreatitis.

Acute Disease↗
PubMed2002

A conjugate of doxorubicin and an analog of Luteinizing Hormone-Releasing Hormone shows increased efficacy against oral and laryngeal cancers.

A doxorubicin and [D-Lys(6)]Luteinizing Hormone-Releasing Hormone (LH-RH) conjugate, AN-152, was designed to target LH-RH receptor positive cells. AN-152 is more potent against a specific group of cancers than doxorubicin and has less peripheral toxicity. This therapy is potentially efficacious against many other types of malignancies. Here, AN-152 was tested on oral (KB) and laryngeal (HEp-2) carcinoma cells. LH-RH receptor presence was demonstrated by displacement binding assays. Cells were treated with 10 nM EGF or left untreated, then exposed to 0-10 microM AN-152. Cytotoxicity was assessed by MTT assay to determine ED(50) values. AN-152 association with the cells was monitored using two-photon laser scanning microscopy. AN-152 was more potent than doxorubicin in both KB and HEp-2 cell lines (P<0.05). Up-regulation of LH-RH receptors by epidermal growth factor (EGF) increased the entry and potency of AN-152 in KB cells, but not in HEp-2 cells. This novel approach may be effective against a variety of cancers.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Antitumor effects of the cytotoxic luteinizing hormone-releasing hormone analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice.

OBJECTIVE: Most human endometrial and ovarian cancers express receptors for luteinizing hormone- releasing hormone. These receptors can be used for targeted chemotherapy with cytotoxic luteinizing hormone-releasing hormone analogs such as AN-152, in which doxorubicin is linked to [D-Lys(6)]luteinizing hormone-releasing hormone. STUDY DESIGN: The antitumor effects of doxorubicin and AN-152 were assessed in vivo in human luteinizing hormone-releasing hormone receptor-positive HEC-1B endometrial cancers and NIH:OVCAR-3 ovarian cancers and in the luteinizing hormone-releasing hormone receptor-negative SK-OV-3 ovarian line. Nude mice bearing these tumors subcutaneously were injected intravenously with saline solution (control), AN-152, or doxorubicin at equimolar doses. Luteinizing hormone-releasing hormone receptor expression in tumors and specimens of human reproductive (n = 5) and nonreproductive (n = 15) normal tissues and in hematopoietic stem cells were analyzed with reverse transcriptase-polymerase chain reaction and radioligand binding assay. RESULTS: The tumor volumes of luteinizing hormone-releasing hormone receptor-positive HEC-1B and NIH:OVCAR-3 cancers were reduced significantly (P <.001) 1 week after treatment with AN-152 at 700 nmol/20 g or at 300 nmol/20 g. No toxic side effects were observed. Treatment with doxorubicin arrested tumor growth but did not reduce tumor volume. Doxorubicin at 700 nmol/20 g caused a high mortality rate and at 300 nmol/20 g (8.7 mg/kg) caused a loss of body weight, but no deaths occurred. The growth of luteinizing hormone-releasing hormone receptor-negative SK-OV-3 cancers was not affected by AN-152. Normal human nonreproductive tissues, hematopoietic stem cells, and vaginal tissue did not express luteinizing hormone-releasing hormone receptors, but luteinizing hormone-releasing hormone receptors were found in the ovary, fallopian tube, cervix, endometrium, and myometrium. CONCLUSION: Targeted chemotherapeutic luteinizing hormone-releasing hormone analog AN-152 is more effective and less toxic than cytotoxic radical doxorubicin on luteinizing hormone-releasing hormone receptor-positive tumors. AN-152 could be considered for targeted chemotherapy in patients with ovarian or endometrial cancers.

Animals↗