piperidines and Carcinoma

Vandetanib is a promising anticancer target agent for treating advanced carcinomas, such as non-small-cell lung cancer (NSCLC) and breast cancer. Rash is a frequently reported adverse event of vandetanib. We conducted this meta-analysis to determine the incidence rate and overall risks of all-grade and high-grade rash with vandetanib in NSCLC patients.. PubMed, Embase, Web of Science, American Society of Clinical Oncology, and Cochrane Library were systematically searched to identify studies with vandetanib and rash in NSCLC patients. Data were extracted to calculate the pooled incidence of all-grade and high-grade (grade ≥3) rash caused by vandetanib treatment.. Nine randomized controlled trials involving 4893 patients met the inclusion criteria and were included in this meta-analysis. The overall incidence of all-grade and high-grade rash caused by vandetanib treatment was 46% (95% CI: 37.1%, 54.8%), and 3.2% (95% CI: 1.4%, 5.1%), respectively. The risk ratios (RR) of all-grade and high-grade rash for vandetanib treatment versus control treatment were 2.35 (95% CI: 1.20, 4.61; P < .001) and 4.68 (95% CI 1.42, 15.37; P < .001), respectively. Subgroup analysis suggested that the increased risk of all-grade rash was clear across all subgroups, including first-line/second-line therapy, phase 2/phase 3 trial, sample size 200, a dosage of 100 or 300 mg, and monotherapy/combination therapy. However, for the high-grade rash, vandetanib did not increase the risk of rash when it was used in first-line therapy, or in a phase II trial, or in a trial with sample size <200.. This study suggests that vandetanib was associated with a significantly increased risk of rash. Therefore, early recognition and appropriate monitoring should be taken when NSCLC patients were treated with vandetanib.

Topics: Antineoplastic Agents; Carcinoma; Carcinoma, Non-Small-Cell Lung; Exanthema; Humans; Incidence; Inflammatory Breast Neoplasms; Neoplasm Staging; Piperidines; Quinazolines; Randomized Controlled Trials as Topic; Severity of Illness Index

Background CD30+ lymphoproliferative disorders are rare and may feature a wide variety of presentations that mimic other conditions. Purpose A man with metastatic papillary thyroid carcinoma to skin who subsequently developed cutaneous anaplastic large cell lymphoma is described. Methods The PubMed medical database was used to search the following terms separately and in combination: ALCL, anaplastic large cell lymphoma ALCL, cutaneous anaplastic large cell lymphoma CALCL, cutaneous t-cell lymphoma CTCL, large t-cell lymphoma LTCL, lymphoproliferative, lymphomatoid papulosis LyP, mimic, papillary, thyroid cancer. Results CD30+ cutaneous anaplastic large cell lymphoma was diagnosed in a man with metastatic papillary thyroid carcinoma based on the temporal, histologic, and immunochemical features of an enlarging lesion. To the best of our knowledge, this is the initial description of a CD30+ lymphoproliferative disorder occurring in a patient with primary carcinoma of the thyroid. Conclusion Cutaneous lesions may present with various morphologies. Our patient had a previous history of metastatic papillary thyroid carcinoma to skin. His new chest lesion was originally suspected to be either an infection or a cutaneous metastasis. Multiple biopsies, not only for microscopic evaluation but also cultures for infectious organisms, were performed. Unexpectedly, a CD30+ lymphoproliferative disorder was diagnosed; subsequently the tumor spontaneously resolved. Therefore, when skin lesions appear that have more than one clinical presentation, it may be prudent for the clinician to collect representative samples of each distinct morphology to assure that an accurate diagnosis is established.

Topics: Aged; Carcinoma; Carcinoma, Papillary; Humans; Immunohistochemistry; Ki-1 Antigen; Lymphoma, Large-Cell, Anaplastic; Lymphoproliferative Disorders; Male; Neoplasms, Multiple Primary; Piperidines; Quinazolines; Skin Neoplasms; Thoracic Wall; Thyroid Cancer, Papillary; Thyroid Neoplasms

To investigate the capacity for ZD6474, a small molecule tyrosine kinase inhibitor, to enhance anti-tumor and anti-metastasis effects of radiation on human nasopharyngeal carcinoma (NPC).. NPC cell lines and xenograft models were evaluated following treatment with ZD6474 and radiation alone and in combination compared with untreated control mice.. Treatment with ZD6474 enhanced the anti-proliferative effect of radiation on NPC cell lines as detected by cell proliferation and apoptosis assays. ZD6474 also induced a significant increase in the radiosensitivity of NPC cells, with radiation enhancement ratios (RERs) ranging from 1.2 to 1.6. Despite the cytotoxicity exhibited by NPC cells following radiotherapy, the invasion and migration of NPC cells was found to be unaffected. In contrast, treatment with ZD6474 strongly inhibited the invasion and migration of NPC cells. When the administration of radiation and ZD6474 was investigated in vitro, the ability of ZD6474 to inhibit activation of the pro-survival signaling pathways induced by radiation was demonstrated. In vivo, ZD6474 significantly enhanced the anti-metastasis effects of radiation, while treatment with radiation and ZD6474 was found to be well tolerated and resulted in a strong inhibition of tumor growth.. Our results suggest the combination of radiation and ZD6474 represents a promising strategy for the treatment of human NPC.

Topics: Animals; Apoptosis; Carcinoma; Chemotherapy, Adjuvant; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Piperidines; Protein Kinase Inhibitors; Quinazolines

Historically, systemic therapies for advanced, metastatic thyroid carcinomas have been poorly effective. However, as a result of a confluence of increasing knowledge of the biologic basis for thyroid cancer development and progression, identification of therapeutic agents that could target these biologic abnormalities, and enthusiasm for research by both funding agencies as well as patients, multiple clinical trials have been initiated and successfully completed during the past several years. This article focuses on findings from key studies that reflect the new paradigms for treatment.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Axitinib; Benzamides; Benzenesulfonates; Carcinoma; Clinical Trials as Topic; Drug Delivery Systems; Gefitinib; Humans; Imatinib Mesylate; Imidazoles; Indazoles; Indoles; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinazolines; Sorafenib; Thyroid Neoplasms

Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy.. The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m(2) intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives.. In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months.. In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Disease Progression; Disease-Free Survival; Docetaxel; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Piperidines; Platinum Compounds; Prognosis; Proportional Hazards Models; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinazolines; Risk Factors; Taxoids; Treatment Failure; Urologic Neoplasms; Urothelium

No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting.. In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095.. Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group).. Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted.. AstraZeneca.

Topics: Adenocarcinoma, Follicular; Adolescent; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Carcinoma, Papillary; Diarrhea; Disease-Free Survival; Double-Blind Method; Electrocardiography; ErbB Receptors; Female; Heart Conduction System; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Skin Neoplasms; Survival Analysis; Thyroid Cancer, Papillary; Thyroid Neoplasms; Young Adult

Arzoxifene, a benzothiophene estrogen agonist/antagonist, is being developed for prevention and treatment of osteoporosis and for risk reduction of invasive breast cancer in postmenopausal women.. The effects of arzoxifene 20 mg/d on bone mineral density (BMD), uterine safety, and overall safety were studied in the FOUNDATION study, a 2-yr randomized, placebo-controlled trial including 331 postmenopausal women with normal to low bone mass.. Compared to placebo, arzoxifene significantly increased lumbar spine (+2.9%) and total hip (+2.2%) BMD. Arzoxifene decreased biochemical markers of bone metabolism compared to placebo. Changes in breast density were neutral or slightly decreased in the arzoxifene vs. placebo group. There was no evidence of endometrial hyperplasia or carcinoma in the arzoxifene group as assessed by central review of baseline and follow-up endometrial biopsies. There was no significant change between the groups in endometrial thickness assessed by transvaginal ultrasound. The incidence of uterine polyps and vaginal bleeding was not significantly different between the groups. Vulvovaginal mycotic infection was the only adverse event significantly increased in the arzoxifene vs. placebo group. Hot flushes were not significantly different between the groups.. In postmenopausal women with normal to low bone mass, arzoxifene 20 mg/d increased BMD at the spine and hip and had a neutral effect on the uterus and endometrium.

Topics: Aged; Algorithms; Antineoplastic Agents; Bone and Bones; Bone Density; Breast Neoplasms; Carcinoma; Endometrium; Female; Humans; Middle Aged; Organ Size; Piperidines; Placebos; Postmenopause; Thiophenes

Topics: Carbazoles; Carcinoma; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital.. Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment.. During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment.. About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma; Carcinoma, Medullary; Female; Follow-Up Studies; Heart Failure; Humans; Intestinal Perforation; Kaplan-Meier Estimate; Male; Middle Aged; Oophoritis; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Retrospective Studies; Risk Factors; Sorafenib; Thrombocytopenia; Thyroid Neoplasms; Time Factors; Young Adult

Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.

Topics: Animals; Antibodies, Monoclonal; Apoptosis; Azetidines; B7-H1 Antigen; Carcinoma; CD8-Positive T-Lymphocytes; Cell Cycle Checkpoints; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Drug Therapy; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; Humans; Immunotherapy; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Neoplasm Transplantation; Piperidines

Vandetanib (ZactimaTM) is a novel, orally available inhibitor of both vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinase. In the present study, a line of transgenic mice with a mouse Egfr gene mutation (delE748-A752) corresponding to a human EGFR mutation (delE746-A750) was established. The transgenic mice developed atypical adenomatous hyperplasia to adenocarcinoma of the lung at around 5 weeks of age and died of lung tumors at approximately 17 weeks of age. In the mice treated with vandetanib (6mg/kg/day), these lung tumors disappeared and the phosphorylations of EGFR and VEGFR-2 were reduced in lung tissues to levels comparable to those of non-transgenic control mice. The median overall survival time of the transgenic mice was 28 weeks in the vandetanib-treated group and 17 weeks in the vehicle-treated group. Vandetanib significantly prolonged the survival of the transgenic mice (log-rank test, p＜ 0.01); resistance to vandetanib occurred at 20 weeks of age and the animals died from their lung tumors at about 28 weeks of age. These data suggest that vandetanib could suppress the progression of tumors harboring an activating EGFR mutation.

Topics: Animals; Antineoplastic Agents; Carcinogenesis; Carcinoma; ErbB Receptors; Gene Expression Regulation; Hyperplasia; Lung Neoplasms; Mice; Mice, Transgenic; Mutation; Piperidines; Quinazolines; Signal Transduction; Vascular Endothelial Growth Factor A

We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.. Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo. HGF/Met expression and activation of signaling in NPC cells were detected by using Western blot and immunohistochemistry. Biological evaluation, including wound healing, cell proliferation, and invasion of NPC cells, was also examined, and the correlation between HGF/Met expression of primary and metastatic tumor in NPC patients and clinical prognosis were also analyzed.. Met TKI inhibitor, PF-2341066, inhibited growth of NPC cells in vivo with half maximal inhibitory concentration of 0.79±0.21 μmol/L, and suppressed invasion and migration of NPC cells; also, the inhibition of PF-2341066 was synergized with cisplatin treatment. Compared with the control group, Met TKI inhibited metastasis of transplanted NPC in nude mice (the number of live metastases [mean ± SD]: 5.8±2.2 versus 11.8±2.2, P=0.03; the number of lung metastases: 2.3±1.5 versus 5.3±0.9, P=0.06). HGF was widely expressed in both primary and metastatic lesions while Met expression of metastatic lesions was higher than that of primary lesions (primary lesions: 24.7%; liver metastases: 40%; lung metastases: 29%; lymph node metastases: 29%, P<0.05), and overall survival of NPC patients with higher expression of Met was shorter (P=0.13).. Our results demonstrated that HGF/Met signaling promoted NPC growth, further resulting in metastasis and poor prognosis. Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin. Our study implied that HGF/Met signaling was the potential therapeutic target in NPC, and blockage of the signaling could prevent growth and metastasis of NPC and derive clinical benefit.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cisplatin; Crizotinib; Dose-Response Relationship, Drug; Drug Synergism; Hepatocyte Growth Factor; Humans; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Xenograft Model Antitumor Assays

Early therapeutic effects of anti-angiogenic agent ZD6474 upon nasopharyngeal carcinoma (NPC) in nude mouse were monitored by using intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI). Mice bearing NPC underwent IVIM DWI at baseline and after 1, 3, and 7 days of treatment with ZD6474 or vehicle (n = 12 per group). Parameters of apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion fraction (f), and blood pseudodiffusion coefficient (D*) at different time points were compared between the two groups or within the treated group. In the treated group, the perfusion-related parameters f and D* of the tumors decreased significantly on day 1 while the diffusion-related parameters ADC and D were significantly higher beginning on day 3 compared with the control group. The decreases in f on day 1 and D* on day 3 were moderately correlated with the smaller tumor size change on day 7. Moderate correlations were established between MVD and f and D* as well as between increased TUNEL or decreased Ki-67 index and ADC and D. This study supports that IVIM DWI is sensitive to detect the ZD6474-induced changes in NPC in nude mouse and the f parameter could predict early response to anti-angiogenic treatment.

Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Diffusion Magnetic Resonance Imaging; Humans; Image Processing, Computer-Assisted; Ki-67 Antigen; Mice; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Piperidines; Quinazolines; Radiography; Transplantation, Heterologous

Tyrosine kinase inhibitors (TKIs) are used to treat patients with advanced thyroid cancers. We retrospectively investigated the efficacy of TKIs administered outside of clinical trials in metastatic sites or locally advanced thyroid cancer patients from five French oncology centers.. THERE WERE 62 PATIENTS (37 MEN, MEAN AGE: 61 years) treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%) outside of clinical trials; 22 had papillary, five had follicular, five had Hürthle cell, 13 had poorly differentiated, and 17 had medullary thyroid carcinoma (MTC). Thirty-three, 25, and four patients were treated with one, two, and three lines of TKIs respectively. Primary endpoints were objective tumor response rate and progression-free survival (PFS). Sequential treatments and tumor response according to metastatic sites were secondary endpoints.. Among the 39 sorafenib and 12 sunitinib treatments in differentiated thyroid carcinoma (DTC) patients, partial response (PR) rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line compared with first-line sorafenib or sunitinib therapy (6.7 vs 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment.. This is the largest retrospective study evaluating TKI therapies outside of clinical trials. DTC patients treated with second-line therapy had stable disease as best response, but had a similar median PFS compared with the first-line treatment.

Topics: Adenocarcinoma; Adenocarcinoma, Follicular; Adenoma, Oxyphilic; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Carcinoma, Neuroendocrine; Carcinoma, Papillary; Disease-Free Survival; Female; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Piperidines; Pleural Neoplasms; Protein-Tyrosine Kinases; Pyrroles; Quinazolines; Retrospective Studies; Sorafenib; Sunitinib; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Outcome

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Carcinoma; Carcinoma, Papillary; Female; Humans; Male; Piperidines; Quinazolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Carcinoma; Carcinoma, Papillary; Female; Humans; Male; Piperidines; Quinazolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Topics: Carcinoma; Chemotherapy, Adjuvant; Drug Eruptions; Histamine H2 Antagonists; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Psoriasis; Radiodermatitis; Radiotherapy, Adjuvant; Tongue Neoplasms

Topics: Adenoma; Anti-Obesity Agents; Apoptosis; Carcinoma; Cell Transformation, Neoplastic; Colorectal Neoplasms; Dronabinol; Drug Inverse Agonism; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antineoplastic Agents; Carcinoma; Cell Survival; Colorectal Neoplasms; Dose-Response Relationship, Drug; Humans; Mice; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors

In thyroid cancer (TC), endothelial growth factor (EGF) has been associated with dedifferentiation, tumor cell proliferation, and angiogenesis. Vascular endothelial growth factor (VEGF) has been documented to be the main stimulator of angiogenesis in the thyroid gland. Patients with undifferentiated thyroid cancer are in desperate need of new therapeutic strategies because common protocols of therapy usually fail. The aim of this study, therefore, was to evaluate two tyrosine-kinase inhibitors (TKI, ZD 1839 gefitinib and ZD 6474 vandetanib), directed against the EGF/VEGF receptor for possible antitumor therapy in thyroid cancer.. EGF/VEGF-R was documented in anaplastic (Hth74, C643), follicular (FTC133), and papillary (TPC1) thyroid cancer cell lines by Western blot analysis. The antiproliferative effect of two TKI (0.1-10 microM) on thyroid cancer cell lines in vitro was quantified by MTT assay, the antiangiogenic effect by assessing secretion of VEGF by enzyme-linked immunosorbent assay (R&D Systems). ZD 1839 is mainly directed against EGF-R and ZD 6474 against VEGF-R (AstraZeneca, UK), single applications and combinations of compounds were evaluated.. EGF-R and VEGF-R as well as the phosphorylated receptor were documented in all of the cell lines. Administration of ZD1839 led to an up to 90% reduction of cell number in Hth74, 80% in C643, 50% in FTC133, and 90% in TPC1 (p < 0.05). ZD1839 induced a decrease of VEGF secretion between 30% in C643 and 90% in Hth74. Administration of ZD6474 led to an up to 95% reduction of cell number in Hth74, 85% in C643, 90% in FTC133, and 90% in TPC1 (p < 0.05). The ZD6474 induced decrease of VEGF secretion ranged between 20% (FTC133) and 60% (TPC1). Combinations of IC50 concentrations of TKI showed synergistic effects, resulting in additional inhibition of proliferation between 50 and 90% compared to single drug administration.. The EGF/EGF-R system resembles a powerful VEGF-stimulating pathway in all histiotypes of TC and can be inhibited by TKI. TKI directed against EGF-R as well as VEGF-R inhibit tumor cell proliferation and VEGF secretion in vitro. Combinations of TKI are more effective than strategies using single agents. It is suggested that targeting EGF-R/VEGF-R-mediated pathways may have therapeutic potential in some undifferentiated thyroid cancers.

Topics: Carcinoma; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Gefitinib; Humans; Piperidines; Protein Kinase Inhibitors; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms; Vascular Endothelial Growth Factor A

Today, the most important treatment of advanced prostate cancer is castration; unfortunately, however, the long-term effect of this therapy is insufficient. Recent studies suggest that castration-induced prostate involution could be caused by primary effects in the prostate vasculature; therefore, we examined if antivascular treatments could mimic the effects of castration.. Androgen-independent AT-1 prostate cancer cells were grown inside the ventral prostate in adult rats. Tumor-bearing animals were treated with an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor signaling, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine (ZD6474, AstraZeneca, Södertälje, Sweden), and short-term effects (after 3 days) were compared with those induced by castration.. Castration caused decreased vascular density in the normal tissue surrounding the tumor and consequently increased tumor hypoxia and apoptosis, and moderately decreased tumor growth. ZD6474 treatment resulted in decreased tumor vascular density accompanied by increased tumor hypoxia, apoptosis, and decreased tumor growth, suggesting that castration and antiangiogenic therapy work through similar mechanisms. Interestingly, castration or ZD6474 alone worked by reducing vascular density in the surrounding normal tissue and ZD6474 also in the tumor. Combined treatment with castration + ZD6474 was more effective than castration and ZD6474 alone in inducing tumor hypoxia, apoptosis, necrosis, and decreasing tumor vascular density.. These findings show that a drug that targets the vasculature in the tumor and in the surrounding ventral prostate lobe could mimic and even enhance the effects of castration. Our present findings thus suggest that castration + ZD6474 could be a particularly effective way to treat prostate tumors.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma; Castration; Combined Modality Therapy; Dose-Response Relationship, Drug; Male; Piperidines; Prostatic Neoplasms; Quinazolines; Rats; Xenograft Model Antitumor Assays

The ras oncogenes are among those most frequently found in human cancers. Blocking Ras farnesylation is a promising strategy for arresting cancer growth. Ras activates several signaling pathways with key roles in cellular proliferation, invasion, metastasis and angiogenesis. Furthermore, proteolytic activities of matrix proteinases such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) are regulated by Ras isoforms. Thus, we investigated the effects of SCH-66336, a farnesyltransferase inhibitor, on secretion of components of the plasminogen activation system as well as on the gelatinases MMP-2 and MMP-9, which play pivotal roles in matrix remodeling. SCH-66336 up to 5 microM did not significantly alter the viability of prostate (PC-3) and renal (Caki-1) cancer cells incubated in serum-depleted medium. SCH-66336 partly inhibited the processing of H-Ras, while levels of mature N-Ras and K-Ras remained unaffected. Under these noncytotoxic conditions, uPA and tPA levels were lowered in culture medium but raised in cell lysates, suggesting inhibition of trafficking pathways. In contrast, SCH-66336 had no effect on uPAR expression or on secreted PAI-1 levels. As expected, the reduction of uPA and tPA activities by SCH-66336 inhibited the conversion of plasminogen to plasmin by about 25% in PC-3 cells. SCH-66336 also inhibited the levels of secreted pro-MMP-2 and pro-MMP-9 as well as the release of their inhibitors TIMP-1 and TIMP-2. SCH-66336 decreased both the adhesion and even more so the migration of PC-3 cells on gelatin. Thus, SCH-66336 inhibited farnesylation in both cancer cell types, and H-Ras functions should be reduced by the drug. In addition, the lower levels of secreted proteinases in the presence of SCH-66336 suggest that reduced matrix remodeling and cell migration should occur in treated tumors.

Topics: Alkyl and Aryl Transferases; Carcinoma; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Survival; Culture Media; Dose-Response Relationship, Drug; Down-Regulation; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Farnesyltranstransferase; Fibrinolysin; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Kinetics; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Piperidines; Plasminogen; Protein Isoforms; Proto-Oncogene Proteins p21(ras); Pyridines; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator

Farnesyl protein transferase inhibitors (FTIs) have demonstrated clinical activity in certain solid tumors and hematological malignancies. Little is known about mechanisms of resistance to these agents. To provide a basis for better understanding FTI resistance, the colorectal carcinoma cell line HCT 116 was selected by stepwise exposure to increasing 4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide (SCH66336) concentrations. The resulting line, HCT 116R, was 100-fold resistant to SCH66336 and other FTIs, including methyl {N-[2-phenyl-4-N[2(R)-amino-3-mercaptopropylamino] benzoyl]}-methionate (FTI-277), but was less than 2-fold resistant to the standard agents gemcitabine, cisplatin, and paclitaxel. Accumulation of the unfarnesylated forms of prelamin A and HDJ-2, two substrates that reflect farnesyl transferase inhibition, was similar in FTI-treated parental and HCT 116R cells, indicating that alterations in drug uptake or inhibition of farnesyl protein transferase is not the mechanism of resistance. Changes in signal-transduction pathways that might account for this resistance were examined by immunoblotting and confirmed pharmacologically. There was no difference in activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase pathway or sensitivity to the MEK1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059) in HCT 116R cells. In contrast, increased phosphorylation of the molecular target of rapamycin (mTOR) and its downstream target p70 S6 kinase and increased levels of Akt1 and Akt2 were demonstrated in HCT 116R cells. Further experiments demonstrated that the mTOR inhibitor rapamycin selectively sensitized HCT 116R cells to SCH66336 but not to gemcitabine, cisplatin, or paclitaxel. These findings provide evidence that alterations in the phosphatidylinositol-3 kinase/Akt pathway can contribute to FTI resistance and suggest a potential strategy for overcoming this resistance.

Topics: Alkyl and Aryl Transferases; Carcinoma; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Inhibitors; Farnesyltranstransferase; HCT116 Cells; Humans; Piperidines; Pyridines

The objective was to determine if EM-652, a novel selective estrogen receptor modulator (SERM) having highly potent and pure antiestrogenic activity in the mammary gland could cause complete regression of the majority of human breast cancer xenografts in nude mice.. Human breast cancer ZR-75-1 xenografts were used as model in nude mice.. EM-652 not only prevented estrogen-induced tumor growth but it reduced tumor size to 20% of the pretreatment value. Complete disappearance of the tumors was observed in 65% (106/163) of tumors. No tumor progressed. Most importantly, 93% of the tumors which had become undetectable under EM-652 treatment did not reappear when exposed to estrogen challenge for 12 weeks, thus achieving an overall 61% cure rate.. The present data demonstrate that EM-652 is strongly cytotoxic or tumorocidal and not only cytostatic or tumorostatic in estrogen-sensitive breast cancer, thus changing the paradigm of a tumorostatic role of estrogen blockade established with tamoxifen. These findings support the use of such a compound for more efficient breast cancer prevention and therapy.

Topics: Analysis of Variance; Animals; Breast Neoplasms; Carcinoma; Estrogens, Non-Steroidal; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Piperidines; Recurrence; Remission Induction; Selective Estrogen Receptor Modulators

Matrix metalloproteinase-2 (MMP-2) plays a critical role in tumor cell invasion and metastasis. Inhibitors of this enzyme effectively suppress tumor metastasis in experimental animals and are currently being tested in clinical trials. MMP-2 transcriptional regulation is a part of a delicate balance between the expression of various extracellular matrix (ECM) constituents and ECM degrading enzymes. Halofuginone, a low-molecular-weight quinazolinone alkaloid, is a potent inhibitor of collagen type alpha1 (I) gene expression and ECM deposition. We now report that expression of the MMP-2 gene by murine (MBT2-t50) and human (5637) bladder carcinoma cells is highly susceptible to inhibition by halofuginone. Fifty percent inhibition was obtained in the presence of as little as 50 ng/ml halofuginone. This inhibition is due to an effect of halofuginone on the activity of the MMP-2 promoter, as indicated by a pronounced suppression of chloramphenicol acetyltransferase activity driven by the MMP-2 promoter in transfected MBT2 cells. There was no effect on chloramphenicol acetyltransferase activity driven by SV40 promoter in these cells. Halofuginone-treated cells failed to invade through reconstituted basement-membrane (Matrigel) coated filters, in accordance with the inhibition of MMP-2 gene expression. A marked reduction (80-90%) in the lung colonization of MBT2 bladder carcinoma cells was obtained after the i.v. inoculation of halofuginone-treated cells as compared with the high metastatic activity exhibited by control untreated cells. Under the same conditions, there was almost no effect of halofuginone on the rate of MBT2 cell proliferation. These results indicate that the potent antimetastatic activity of halofuginone is due primarily to a transcriptional suppression of the MMP-2 gene, which results in a decreased enzymatic activity, matrix degradation, and tumor cell extravasation. This is the first description, to our knowledge, of a drug that inhibits experimental metastasis through the inhibition of MMP-2 at the transcriptional level. Combined with its known inhibitory effect on collagen synthesis and ECM deposition, halofuginone is expected to exert a profound anticancerous effect by inhibiting both the primary tumor stromal support and metastatic spread.

Topics: Animals; Antineoplastic Agents; Carcinoma; Collagen; Dose-Response Relationship, Drug; Drug Combinations; Gelatin; Humans; Laminin; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C3H; Neoplasm Invasiveness; Neoplasm Transplantation; Piperidines; Promoter Regions, Genetic; Proteoglycans; Quinazolines; Quinazolinones; Tumor Cells, Cultured; Urinary Bladder Neoplasms

In medullary carcinoma of the thyroid (MTC), drug resistance remains the major obstacle to effective chemotherapy. In this work, we studied the effect of S9788 on doxorubicin (DOX) efficiency in a MTC cell line (TT cells) injected in nude mice. After two passages, TT cells were injected in 40 nude mice divided into four groups [controls and groups receiving DOX alone (10 mg/kg), S9788 alone (50 mg/kg) or both DOX + S9788]. The weight of the mice, tumoral volume (TV), doubling time (DT) of the tumor and survival time of mice were evaluated in each group. In addition, the efficiency of DOX with or without S9788 was assessed by the inhibition of tumoral growth and specific growth delay. In vitro, glycoprotein P 170 (P-gp) was detected on tissular sections and on tumoral cells by immunocytochemistry or flow cytometry with several monoclonal antibodies: JSB1, MRK 16, C219 and UIC2. In vivo the weight of the mice decreased slightly with DOX and dropped dramatically with DOX + S9788. The DT of the tumors increased with DOX over controls (22.5 +/- 8.5/12.7 +/- 3.9 days) and showed a higher value with DOX + S9788 (29.2 +/- 11.4 days). Inhibition of tumoral growth, 89% with DOX, fell to 47.6% with DOX + S9788. Specific growth delay increased with the double treatment (130 versus 75% with DOX alone). In vitro, P-gp was not detected on tissular sections and cells whatever the method and the antibody used. In conclusion, S9788 potentiates the efficiency of DOX treatment in vivo. The absence of P-gp may result from the absence of translation of the MDR1 gene. The reversal effect of S9788 may involve another resistance mechanism such as the MDR Sister of MRP.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma; Doxorubicin; Drug Synergism; Female; Humans; Mice; Mice, Nude; Piperidines; Thyroid Neoplasms; Triazines; Tumor Cells, Cultured

Bioreducible anti-tumour agents are prodrugs which are intended to be inactive in normal cells, but are able to undergo metabolic reduction in cancer cells to produce toxic species that can damage biomolecules. A series of N-oxides of heterocyclic aliphatic amines were designed and prepared as mentioned below as bioreducible drugs based on the reported anti-cancer activity of 2,6-bis(halomethyl)piperidines. In order to study structure-activity relationships in these conformationally restricted nitrogen mustards, samples of cis- and trans-2,6-dihydroxymethyl-N-methylpiperidine were prepared and converted into a number of carbamate or halogen derivatives. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation. The corresponding N-oxides were also prepared for comparison in cytotoxicity tests. In total, 21 new compounds were synthesized plus cis-N-methyl-2,6-bis(chloromethyl)-piperidine (prepared previously but lacking spectroscopic data) and tested against two human colon carcinoma cell lines, HT 29 (high DT-diaphorase) and BE (no DT-diaphorase), under oxic and hypoxic conditions. The majority of the free bases were equally toxic against both cell lines. The most toxic compounds were cis- and trans-N-methyl-2,6-bis(bromomethyl)piperidine with oxic IC50 values between 6 and 11 microM against both cell lines. The N-oxides were relatively non-toxic under both oxic and hypoxic conditions apart from the N-oxide of trans-N-methyl-2,6-bis(bromomethyl)-piperidine. Their low toxicity suggested that the N-oxides are not reduced under hypoxic conditions. We conclude that: (i) 2,6-disubstituted N-methylpiperidine derivatives are chemically versatile cytotoxic entities that are suitable for prodrugging to enhance their therapeutic selectivity; and (ii) N-oxide prodrugs of these compounds are deactivated chemically and display reduced cytotoxicity compared to the parent amines but are apparently not reduced under hypoxic conditions. At least in the colorectal cell lines tested the latter issue would need to be addressed by modifying the redox properties in future work to progress this approach.

Topics: Antineoplastic Agents, Alkylating; Biotransformation; Carcinoma; Cell Hypoxia; Colorectal Neoplasms; Dihydrolipoamide Dehydrogenase; Humans; Neoplasm Proteins; Nitrogen; Oxidation-Reduction; Oxides; Piperidines; Prodrugs; Structure-Activity Relationship; Tumor Cells, Cultured

1. The effects of seven muscarinic receptor antagonists were used to characterize the receptors which mediate carbachol-evoked contractions of intertaenial circular and taenial longitudinal muscle in human isolated colon. The effects of these antagonists were studied upon colon contractions induced by cumulatively added carbachol which had mean EC50 values of 11.7 +/- 2.3 microM (n = 8) and 12.6 +/- 2.3 microM (n = 8) respectively upon circular and longitudinal smooth muscle. 2. All antagonists displaced concentration-response curves to carbachol to the right in a parallel manner. The maximum concentration of each antagonist added (30 nM-10 microM) did not significantly suppress the maximum response. 3. In circular muscle, the M3 muscarinic receptor antagonists, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), hexahydrosiladiphenidol (HHSiD) and para-fluoro-hexahydrosiladiphenidol (p-F-HHSiD) inhibited responses with pA2 values of 9.41 +/- 0.23, 7.17 +/- 0.07, 6.94 +/- 0.18 respectively. The M2 muscarinic receptor antagonist, AF-DX 116, the M2/M4 muscarinic receptor antagonist, himbacine, and the M1 muscarinic receptor antagonist, pirenzepine, yielded pA2 values of 7.36 +/- 0.43, 7.47 +/- 0.14 and 7.23 +/- 0.48 respectively. The non-selective antagonist, atropine, had a pA2 of 8.72 +/- 0.28. 4. In longitudinal muscle 4-DAMP, HHSiD, p-F-HHSiD, AF-DX 116, himbacine and pirenzepine gave pA2 values of 9.09 +/- 0.16, 7.45 +/- 0.43, 7.44 +/- 0.21, 6.44 +/- 0.1, 7.54 +/- 0.40, 6.87 +/- 0.38 respectively. Atropine yielded a pA2 value of 8.60 +/- 0.08. 5. The pharmacological profile of antagonist affinities at the muscarinic receptor population responding to muscarinic agonist-evoked contraction is similar to that widely accepted as characterizing the activation of an M3 muscarinic receptor subtype, although pA2 values of some antagonists are lower than that seen in other investigations.

Topics: Alkaloids; Atropine; Carbachol; Carcinoma; Colon; Colonic Neoplasms; Dose-Response Relationship, Drug; Furans; Humans; In Vitro Techniques; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Naphthalenes; Piperidines; Pirenzepine

Previous data indicated that opioid receptors occur in both neural and nonneural human tumors. However, it has recently been shown that some of the putative opioid binding may be attributable to sigma sites. In this study the occurrence of sigma and opioid receptors in nonneural human tumors was assessed. The neoplasms included renal and colon carcinomas and a sarcoma. [3H]1,3-di-o-tolylguanidine was used to assay sigma receptors by homologous competition binding assays, which when analyzed provided dissociation constant and receptor density values. Opioid binding was measured with [3H]-(-)-ethylketocyclazocine, a ligand which interacts with mu, delta, and kappa subtypes. Fresh surgical specimens were obtained from 9 human neoplasms, selected for their large size, and compared with nonmalignant tissues. All 9 tumors contained sigma sites, and dissociation constant values were within the range of 27-83 nM. Occasionally, two-site fit the data better than one-site binding, suggesting the presence of multiple sigma sites. Opioid binding was not detected. Intratumoral variability was evaluated by sampling several locations on the periphery of the mass and one in the center. Each of the samples was bisected, with a portion reserved for histological examination to correlate morphological features with receptor data. Changes in sigma binding were not associated with the extent of fibrosis, viability, or necrosis. Receptor density values displayed moderate intra- and intertumoral variation (coefficients of variation, 8-39 and 27-49%, respectively). More important, sigma binding in tumors was found to be greater than or equal to 2-fold higher than that of control nonmalignant tissue.

Topics: Binding, Competitive; Carcinoma; Colonic Neoplasms; Guanidines; Humans; In Vitro Techniques; Kidney Neoplasms; Neoplasms; Piperidines; Receptors, Opioid; Receptors, sigma; Sarcoma

Topics: Animals; Carcinoma; Carcinoma, Squamous Cell; Female; Male; Microscopy, Electron; Nasal Cavity; Neoplasms, Experimental; Nitrosamines; Nose Neoplasms; Olfactory Bulb; Piperidines; Rats

Three chlorinated nitrosopiperidines, 3-chloro-, 4-chloro-, and 3,4-dichloronitrosopiperidine, were administered to groups of 20 male Fischer 344 rats at a concentration of 0.17 mM in drinking water. Treatment with the monochloro compounds lasted for 30 weeks, while treatment with the dichloro compound lasted for 21 weeks. Almost all of the animals died with esophageal tumors. There was also a significant incidence of tumors of the forestomach and tongue in the rats treated with the monochloro compounds. Using the rate of death of the animals with tumors as an index, the relative potency of the three compounds increases from 3-chloro- to 4-chloro- to 3,4-dichloronitrosopiperidine.

Topics: Animals; Carcinogens; Carcinoma; Drinking; Esophageal Neoplasms; Male; Nitrosamines; Papilloma; Piperidines; Rats; Stomach Neoplasms; Time Factors; Tongue Neoplasms

The authors carried out experiments on mice DBA/2 and BDF1 with leucosis L1210 and lung carcinoma of Lewis and found that psycotropic preparations tempidone and caffeine did not manifest antitumorous effect and toxicity after the used doses and scheme of treatment. Tempidone enhanced antitumorous action of small and mean doses of cyclophosphamide in mice with leucosis L1210. In the triple combination (tempidone, caffeine and cycl phosamide) the caffeine enhanced this action of tempidone without raising toxicity in mice with leucosis L1210, but not in mice with lung carcinoma of Lewis.

Topics: Animals; Caffeine; Carcinoma; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Female; Leukemia L1210; Liver Neoplasms; Male; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Piperidines; Piperidones; Psychotropic Drugs; Tosyl Compounds; Triacetoneamine-N-Oxyl

Topics: Autonomic Nerve Block; Benzimidazoles; Carcinoma; Celiac Plexus; Female; Glycerol; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Pain; Palliative Care; Phenols; Piperidines; Sigmoid Neoplasms

Topics: Antineoplastic Agents; Carcinoma; Cell Line; Cells, Cultured; Humans; In Vitro Techniques; Indolizines; Isoquinolines; Mouth Neoplasms; Neoplasms, Experimental; Phenanthrenes; Piperidines

Topics: Acid Phosphatase; Adenocarcinoma; Alkaline Phosphatase; Animals; Carcinoma; Carcinoma, Papillary; Carcinoma, Squamous Cell; Cell Division; Cell Transformation, Neoplastic; Hyperplasia; Injections, Subcutaneous; Male; Nasal Mucosa; Neoplasms, Experimental; Nitroso Compounds; Nose Neoplasms; Papilloma; Piperidines; Rats; Thymidine; Tritium

Topics: Animals; Carcinoma; Culture Techniques; Fibroblasts; Galantamine; Humans; Isoquinolines; Laryngeal Neoplasms; Mice; Nitrofurans; Piperidines

Topics: Carcinogens; Carcinoma; Ethmoid Sinus; Morpholines; Nitrosamines; Nitroso Compounds; Paranasal Sinus Neoplasms; Piperazines; Piperidines; Rats; Research; Toxicology