dihydropyridines and Neoplasms

Nowadays, heterocyclic compounds act as a scaffold and are the backbone of medicinal chemistry. Among all of the heterocyclic scaffolds, 1,4-Dihydropyridine (1,4-DHP) is one of the most important heterocyclic rings that possess prominent therapeutic effects in a very versatile manner and plays an important role in synthetic, medicinal, and bioorganic chemistry. The main aim of the study is to review and encompass relevant studies related to 1,4-DHP and excellent therapeutic benefits of its derivatives. An extensive review of Pubmed-Medline, Embase and Lancet's published articles was done to find all relevant studies on the activity of 1,4-DHP and its derivatives. 1,4-DHP is a potent Voltage-Gated Calcium Channel (VGCC) antagonist derivative which acts as an anti-hypertensive, anti- anginal, anti-tumor, anti-inflammatory, anti-tubercular, anti-cancer, anti-hyperplasia, anti-mutagenic, anti-dyslipidemic, and anti-ulcer agent. From the inferences of the study, it can be concluded that the basic nucleus, 1,4-DHP which is a voltage-gated calcium ion channel blocker, acts as a base for its derivatives that possess different important therapeutic effects. There is a need of further research of this basic nucleus as it is a multifunctional moiety, on which addition of different groups can yield a better drug for its other activities such as anti-convulsant, anti-oxidant, anti-mutagenic, and anti-microbial. This review would be significant for further researches in the development of several kinds of drugs by representing successful matrix for the medicinal agents.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Antihypertensive Agents; Antineoplastic Agents; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Heterocyclic Compounds; Neoplasms; Ulcer

The overexpression of permeability-glycoprotein (P-gp) and other drug transporters (ATP-binding cassette) confers a multidrug resistance (MDR) phenotype on cells in various diseases, including many forms of cancer. Development of MDR is one of the main reasons of failure in malignant tumour chemotherapy, as tumour cells, by increasing drug efflux, acquire cross-resistance to many structurally and functionally unrelated anticancer agents, which therefore never achieve effective intracellular concentrations. Endeavouring to find MDR-reverters is a crucial task for exploring new anti-cancer therapeutic intervention. Although many P-gp inhibitors have so far been identified, it is widely recognised that their interaction with P-gp is a complex process and, presently, the details of the mechanisms of action are still a matter of debate. These compounds turned out, however, to be of limited clinical usefulness owing to their inherent pharmacological activities (first generation compounds) and their accessory, inhibiting activity on CYP enzyme system (second generation compounds). Moreover, recent advances of the knowledge on P-gp structure and function and on the mechanisms of P-gp inhibition will prove fruitful for the development of novel therapeutically effective P-gp inhibitors. A dibenzoyl-1,4-dihydropyridine compound (DP7) has been shown to be a powerful P-gp inhibitor, almost devoid of cardiovascular effects, but capable of inhibiting liver CYP3A. DP7 is considered a lead compound for the development of novel dihydropyridines which do not affect CYP enzyme system but still retain the activity towards ABC-efflux transporters.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Dihydropyridines; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Permeability

The main genetic polymorphisms affecting the metabolism and transport of cytotoxic drugs are discussed in this review. Likely future approaches to pharmacogenetics and emerging technologies, such as tumor classification using microarray analysis, are also considered.

Topics: Antineoplastic Agents; Arylamine N-Acetyltransferase; Cytochrome P-450 Enzyme System; Cytotoxins; Dihydropyridines; Glucuronosyltransferase; Humans; Methyltransferases; Neoplasms; Oxidoreductases; Pharmacogenetics; Polymorphism, Genetic

This is the first clinical study of the MEK1/2 inhibitor AZD8330 (ARRY-424704). This phase I study defined the maximum tolerated dose (MTD) and assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8330 in patients with advanced malignancies.. Patients with refractory cancer or cancer with no standard therapy received either once-daily (OD) or twice-daily (BID) oral AZD8330 on day 1 followed by a 7-day washout period and continuous dosing from day 8. The starting dose was 0.5 mg with dose escalations in subsequent cohorts until a non-tolerated dose was reached.. Eighty-two patients received AZD8330 across 11 cohorts. The most frequent AZD8330-related adverse events were acneiform dermatitis (13/82, 16%), fatigue (11/82, 13%), diarrhoea (11/82, 13%) and vomiting (9/82, 11%). Four patients experienced dose-limiting toxicities: mental status changes (40 mg OD; 2/9 patients and 60 mg OD; 1/3) and rash (20 mg BID; 1/9). The MTD was defined as 20mg BID. AZD8330 exposure increased approximately proportionally with dose across the dose range 0.5-60 mg OD. Dose-dependent modulation of phosphorylated ERK in peripheral blood mononuclear cells (PBMCs) was observed at doses ≥3 mg. One patient had a partial response and thirty-two (39%) had stable disease, with a duration >3 months in 22 patients, assessed by Response Evaluation Criteria in Solid Tumors.. AZD8330 has a manageable toxicity profile at the MTD of 20 mg BID, and target inhibition was confirmed in PBMCs. One patient with malignant melanoma had a partial response.

Topics: Acne Vulgaris; Adolescent; Adult; Area Under Curve; Dermatitis; Diarrhea; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Metabolic Clearance Rate; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Treatment Outcome; Vomiting; Young Adult

Dexniguldipine (DNIG) is the R-enantiomer of the dihydropyridine derivate niguldipine. DNIG showed a binding affinity to the P-glycoprotein (P-gp) and therefore it is to be assumed to block the P-gp pumping mechanism. This open phase I study was conducted to determine the maximal tolerated dose (MTD) and safety of intravenously administered DNIG alone and in combination with vinblastine in patients with a metastatic or locally advanced cancer. Additionally, serum levels of DNIG were assessed and compared between dosage groups to investigate the intravenous dose linearity. The study was divided into two parts concerning DNIG administration. In part I the patients received DNIG for four hours daily over four consecutive days and additionally 0.15 mg/kg vinblastine at day 3. Treatment was started with 1 mg/kg/4h, and whenever the drug was well tolerated the dosage was increased. In part II the patients received up to three courses of a four-hour infusion (5 and 7 mg/kg/4h) of DNIG followed by a continuous infusion for 48 hours (5 and 7 mg/kg/24h). Twenty-six patients entered this trial and were given at least one infusion of DNIG; vinblastine was given immediately after the 4-hour infusion. One to seven courses and dosages from 1-11 mg/kg were administered. In five patients the dose limiting toxicity was seen in cardiovascular adverse events such as a drop in blood pressure, decreased heart rate and in one patient an AV block III. Most frequent adverse events were nausea, dizziness, vomiting, peripheral paresthesia, atactic gait, mild constipation, polyuria, hypocalcemia; all disappeared within 24 hours after discontinuation of infusion. A linear increase in DNIG serum concentration with increasing doses was found following intravenous infusion of DNIG over a four-hour period. Long-term infusion regimes over a period of two or five days resulted in reasonably constant DNIG serum levels. MTD was determined at 5 mg/kg/4h. It is to be assumed that the MTD for continuous infusion of DNIG is higher than 5 mg/kg/24h, but this was not followed up in the study and must be the aim of a later trial.

Topics: Adult; Aged; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Vinblastine

Dexniguldipine-HCl is a new dihydropyridine compound that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. The purpose of this trial was to determine the toxicity and pharmacokinetics of dexniguldipine and to establish a recommended dose for phase II trials. A total of 37 patients with cancer were treated with oral dexniguldipine in increasing doses for up to 7 days. The main parameters evaluated were subjective tolerance and laboratory and cardiovascular parameters (blood pressure and ECG). Blood samples were drawn for analysis of the drug's pharmacokinetics. Dizziness and nausea were the major adverse events observed in seven patients, but episodes were generally mild and not clearly dose-related. Vomiting occurred in one patient. Hypotensive effects and orthostatic dysregulation were observed in some patients but were not considered to be dose-limiting. Therefore, no dose-limiting toxicity was found and the maximally tolerable dose could not be determined. Pharmacokinetic data showed wide interindividual variation and a dose-dependent increase in steady-state serum concentrations at doses of up to 1,000 mg daily, with no clear further increase being observed at higher doses. Consistently high concentrations were achieved with the 2,500-mg dose. Despite the lack of dose-limiting toxicity, higher doses of dexniguldipine do not appear to be useful for clinical evaluation because of the pharmacokinetic properties of the compound: therefore, 2,500 mg/day is recommended as the daily dose for phase II trials.

Topics: Administration, Oral; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Dihydropyridines; Dose-Response Relationship, Drug; Headache; Humans; Metabolic Clearance Rate; Nausea; Neoplasms; Vertigo

Dexniguldipine-HCl is a new dihydropyridine derivative with antineoplastic activity and potency for overcoming multidrug resistance. In this pharmacokinetic study the bioavailability of 3 doses of an oral formulation of dexniguldipine was to be determined. Fourteen patients with malignant disease not eligible for higher priority treatment and sufficient general condition were included. In 12 patients all pharmacokinetic investigations were available for evaluation. A single 4-h infusion of 2 mg per kg body weight of dexniguldipine was given as reference. Thereafter 3 increasing oral dosages (750, 1,500, 2,250 mg/d) were given on a 3-time daily basis for 3 consecutive weeks. On day 7 (under steady state conditions) of each period, a pharmacokinetic profile was done. Absolute bioavailability at the 3-dose levels was 3, 4, and 5%, respectively, thus slightly increasing with dose, but generally low. After intravenous administration terminal half life was 22.4 h, clearance 36.9 l/h and volume of distribution 1,193 1. Toxicity was tolerable with main adverse events being loss of appetite, nausea, and vomiting. Cardiovascular effects and a decrease in serum calcium were reported in several patients. Patients were allowed to continue treatment if a benefit was expected, and 2 patients showed tumor regression during treatment. One patient with renal cell carcinoma achieved a partial remission. Bioavailability of this oral formulation seems too low for routine clinical use, despite the fact that clinical effects have been observed.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antineoplastic Agents; Biological Availability; Dihydropyridines; Dose-Response Relationship, Drug; Drug Evaluation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Reference Standards; United States; World Health Organization

Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8

Topics: Animals; Azetidinecarboxylic Acid; Calcium Channel Blockers; CD47 Antigen; Cell Line, Tumor; Cricetinae; Dihydropyridines; Disease Models, Animal; Drug Repositioning; Gene Expression Regulation, Neoplastic; Humans; Immunity, Innate; Immunotherapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Targeted Therapy; Neoplasms; Receptors, Immunologic; Receptors, Virus; T-Lymphocytes

The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of β-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the β-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for β-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.

Topics: A549 Cells; Animals; beta Catenin; Biphenyl Compounds; Cell Line, Tumor; Chromatin; Dihydropyridines; DNA Damage; Female; Glutathione; Histone-Lysine N-Methyltransferase; Histones; Homeostasis; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Myeloid-Lymphoid Leukemia Protein; Neoplasms; Promoter Regions, Genetic; Protein Interaction Domains and Motifs; Protein-Arginine N-Methyltransferases; Reactive Oxygen Species; Repressor Proteins; Transcriptional Activation

1,4-Dihydropyridines (1,4-DHPs) are important as a class of heterocyclic compounds that exhibit wide range of biological actions. Many of its derivatives are already characterized as medicinally important drugs and used worldwide. In this study, we have screened some novel Hantzsch 1,4-DHP compounds using both in silico (QSAR and Pharmacophore) and in vitro (cytotoxic screening). 1,4-DHP showed selective cytotoxicity against five human cancerous cell lines; A375, A549, HeLa, HepG2 and SH-SY5Y but limited effect towards normal skin keratinocyte (HaCaT), lung fibroblast (WL-38) and healthy peripheral blood mononuclear cells. In A375 and HepG2 cells, one of the 1,4-DHP derivative (DHP-8) was found to inhibit cell proliferation, and simultaneously increased the apoptotic population as well as mitochondrial membrane depolarization. Furthermore, the mitochondrial signal was triggered with the activation of cleaved Caspase9, Caspase3 and PARP. The treatment with DHP-8 also increased the expression level of SIRT1, subsequently decreasing the level of pAKT

Topics: A549 Cells; Apoptosis; Dihydropyridines; Gene Expression Regulation, Neoplastic; HeLa Cells; Hep G2 Cells; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Oncogene Protein v-akt; Sirtuin 1; Survivin

The effects of eleven 1,4-dihydropyridine derivatives (DHPs) used alone or together with prooxidant anticancer drug doxorubicin were examined on two cancer (HOS, HeLa) and two nonmalignant cell lines (HMEC, L929). Their effects on the cell growth (

Topics: Animals; Dihydropyridines; Dose-Response Relationship, Drug; Doxorubicin; Drug Screening Assays, Antitumor; Free Radical Scavengers; HeLa Cells; Humans; Mice; Neoplasms; Rats; Wound Healing

A series of 1,4-dihydropyridine based compounds bearing benzylpyridinium moiety have been designed and evaluated for in vitro anticancer activity against glioblastoma U87MG, lung cancer A549 and colorectal adenocarcinoma Caco-2 cell lines using the MTT assay.. Among these compounds, 7b, 7d, 7e, and 7f exhibited potent anticancer activity against the cell lines tested. The cytotoxicity of the synthesized derivatives was compared to standard drugs (carboplatin, gemcitabine, and daunorubicin).. Thus, synthesized 1,4-dihydropyridines can be considered as the encouraging molecules for further drug development as anticancer agents.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dihydropyridines; Drug Screening Assays, Antitumor; Humans; Neoplasms; Structure-Activity Relationship

The multidrug resistance (MDR) of cancer cells has become a great barrier to the success of chemotherapy.. In this study, quantitative structure activity relationship (QSAR) modeling was applied to 46 1,4-dihydropyridine structures (DHPs), and some selected compounds were docked.. QSAR was used to generate models and predict the MDR inhibitory activity for a series of 1,4-dihydropyridines (DHP). The DHPs were built and optimized using the Sybyl program (x1.2 version). Descriptor generation was done by DRAGON package. Docking was carried out using Auto Dock 4.2 software. Multiple linear regression, and partial least square were performed as QSAR modelgeneration methods. External validation, cross-validation (leave one out) and y-randomization were used as validation methods.. The constructed model using stepwise-MLR and GA-PLS revealed good statistical parameters. In the final step all compounds were divided into two parts: symmetric (PLS) and asymmetric (MLR) 1,4-dihydropyridines and two other models were built. The square correlation coefficient (R2) and root mean square error (RMSE) for train set for GA-PLS were (R2 = 0.734, RMSE train = 0.26).. The predictive ability of the models was found to be satisfactory and could be employed for designing new 1,4-dihydropyridines as potent MDR inhibitors in cancer treatment. 1,4- Dihydropyridine ring containing protonable nitrogen as scaffold could be proposed. Sulfur, ester, amide, acyle, ether, fragments are connected to a 1,4-dihydropyridine ring. Phenyl groups (with an electronegative substituent) as a lipophilic part are essential for the inhibitory effect.

Topics: Antineoplastic Agents; Dihydropyridines; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Least-Squares Analysis; Linear Models; Models, Molecular; Molecular Docking Simulation; Neoplasms; Quantitative Structure-Activity Relationship

Modulators of sirtuins are considered promising therapeutic targets for the treatment of cancer, cardiovascular, metabolic, inflammatory, and neurodegenerative diseases. Here we prepared new 1,4-dihydropyridines (DHPs) bearing changes at the C2/C6, C3/C5, C4, or N1 position. Tested with the SIRTainty procedure, some of them displayed increased SIRT1 activation with respect to the prototype 3a, high NO release in HaCat cells, and ameliorated skin repair in a mouse model of wound healing. In C2C12 myoblasts, two of them improved mitochondrial density and functions. All the effects were reverted by coadministration of compound C (9), an AMPK inhibitor, or of EX-527 (10), a SIRT1 inhibitor, highlighting the involvement of the SIRT1/AMPK pathway in the action of DHPs. Finally, tested in a panel of cancer cells, the water-soluble form of 3a, compound 8, displayed antiproliferative effects in the range of 8-35 μM and increased H4K16 deacetylation, suggesting a possible role for SIRT1 activators in cancer therapy.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Cell Proliferation; Dihydropyridines; Enzyme Activation; Humans; Male; Mice; Mitochondria; Neoplasms; Signal Transduction; Sirtuin 1; Skin; Wound Healing

Multidrug resistance (MDR) caused by P-glycoprotein (P-gp, ABCB1, MDR-1) transporter over-expression in cancer cells substantially limits the effectiveness of chemotherapy. 1,4-Dihydropyridines (DHPs) derivatives possess several pharmacological activities. In this study, 18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moieties at C₃ and C₅ positions, respectively, as well as nitrophenyl or hetero aromatic rings at C₄ were synthesized and tested for MDR reversal with the aim of establishing a structure-activity relationship (SAR) for these agents. Effect of these compounds on P-gp mediated MDR was assessed in P-gp over-expressing MES-SA/DX5 doxorubicin resistant cells by flow cytometric detection of rhodamine 123 efflux. MDR reversal was further examined as the alteration of doxorubicin׳s IC₅₀ in MES-SA/DX5 cells in the presence of DHPs by MTT assay and was compared to nonresistant MES-SA cells. Direct anticancer effect was examined against 4 human cancer cells including HL-60, K562, MCF-7 and LS180. Calcium channel blocking (CCB) activity was also measured as a potential side effect. Most DHPs, particularly compounds bearing 3-nitrophenyl (A2B2 and A3B2) and 4-nitrophenyl (A3B1 and A4B1) moieties at C₄ significantly inhibited rhodamine 123 efflux at 5-25 µM, showing that the mechanism of MDR reversal by these agents is P-gp transporter modulation. Same derivatives were also able to selectively lower the resistance of MES-SA/DX5 to doxorubicin. A2B2 bearing ethyl carboxylate at C₅ had also high direct antitumoral effect (IC₅₀ range: 3.77-15.60 μM). Our findings suggest that SAR studies of DHPs may lead to the discovery of novel MDR reversal agents.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Biological Transport; Calcium Channels; Cell Line, Tumor; Dihydropyridines; Doxorubicin; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Inhibitory Concentration 50; Molecular Structure; Neoplasm Proteins; Neoplasms; Stereoisomerism; Structure-Activity Relationship

This paper reports a drug nanovehicle self-assembled from an amine-functionalized block copolymer poly(6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione)-block-poly(1,3-dioxepan-2-one) (PADMC-b-PTeMC), which is prepared by controlable ring-opening block copolymerization attractively in a "one-shot feeding" pathway. The copolymers display high cell-biocompatibility with no apparent cytotoxicities detected in 293T and HeLa cells. Due to their amphiphilic nature, PADMC-b-PTeMC copolymers can self-assemble into nanosized micelles capable of loading anticancer drugs such as camptothecin (CPT) and doxorubicin (DOX). In particular, the outer PADMC shell endows the PADMC-b-PTeMC nanomicelles with pH-dependent control over the micellar morphology, cell uptake efficiency, and the drug release pattern. Confocal inspection reveals the remarkably enhanced cellular internalization of drug loaded micelles by cancerous HeLa cells at relatively lower pH 5.8 simulating the mildly acid microenvironment in tumors. Along with the acidity-triggered volume expansion of micelles, an accelerated CPT release in vitro occurs. The obtained results adumbrate the possibility of completely biodegradable PADMC-b-PTeMC as pH-sensitive drug carriers for tumor chemotherapy.

Topics: Amines; Camptothecin; Dihydropyridines; Doxorubicin; Drug Liberation; HeLa Cells; Humans; Hydrogen-Ion Concentration; Neoplasms; Polymers

In adults, lacidipine seems to have no CYP3A4-inhibiting action. This particular characteristic makes it advantageous when combined with drugs metabolized by CYP3A4, such as cyclosporine. Until now, no data on the efficacy or safety of this calcium antagonist have been available in children. Thirty-nine hypertensive children (age: 0.13-14 years) receiving lacidipine in oncohematology for a mean of 75 days were included in this retrospective study. The causes of high blood pressure were renal tumor (n=7), catecholamine-secreting tumor (n=4), corticoid treatment (n=5), and cyclosporine treatment (n=23). An initial dosage of 0.05 mg/kg/day was sufficient for 41% of the patients. The remaining patients needed to increase the dosage, by steps of 0.03 mg/kg/day, until reaching an average effective dosage of 0.1 mg/kg/day. Lacidipine significantly decreased blood pressure by 30 (±14) mmHg for systolic blood pressure and by 26 (±13) mmHg for diastolic blood pressure. A medication plan with twice-daily administration was not significantly more effective than a single administration per day. Lacidipine was well tolerated, and no toxicity-related withdrawal of treatment occurred. For 22 patients treated with both cyclosporine and lacidipine, renal function was not disturbed over time, suggesting its preservation by lacidipine. No significant increase in cyclosporine blood concentration was detected. Lacidipine seems to be an effective calcium antagonist in pediatric oncohematology, is well tolerated, has a kidney-protector effect and no drug interaction when combined with cyclosporine.

Topics: Adolescent; Antihypertensive Agents; Child; Child, Preschool; Cyclosporine; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glomerular Filtration Rate; Glucocorticoids; Humans; Hypertension; Immunosuppressive Agents; Infant; Male; Neoplasms; Retrospective Studies

Novel series of N-benzyl 1,4-dihydropyridines have been prepared by facile syntheses. All relevant substituents of the molecular scaffold have been varied. The resulting compounds were biologically evaluated as P-glycoprotein (P-gp) inhibitors. Substitutions of the N-benzyl residue favour biological activity beside respective 3-ester functions. Most active compounds were further evaluated as multidrug resistance (MDR) modulators to restore the cytotoxic properties of varying daunorubicin applications.

Topics: Animals; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Survival; Daunorubicin; Dihydropyridines; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Mice; Neoplasms; Structure-Activity Relationship

A number of a new pyridine thioglycosides were synthesized via reaction of piperidinium salts of dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-alpha-D-gluco- and galactopyranosyl bromide. The antitumor activities of the synthesized compounds were evaluated utilizing two different human cell lines. Some of the tested compounds showed high inhibition of human cell lines. The detailed synthesis, spectroscopic data and antitumor activities for the synthesized compounds were reported.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Dihydropyridines; Drug Screening Assays, Antitumor; Humans; Hydrogenation; Male; Mice; Molecular Structure; Neoplasms; Thioglycosides

A series of N-substituted cage dimeric 1,4-dihydropyridines 3a-e was evaluated as inhibitors of membrane efflux pump P-glycoprotein (P-gp) in multidrug resistant (mdr) cancer cells. Structure-activity relationships (SAR) and cytotoxic properties are discussed. Effective concentrations for overcoming mdr have been demonstrated in competition studies with the P-gp substrate epirubicin.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Cell Proliferation; Dihydropyridines; Dimerization; Hydroxylation; Methylation; Mice; Molecular Structure; Neoplasms; Structure-Activity Relationship

P-glycoprotein-mediated drug efflux is one of the major causes of the cancer multidrug resistance (MDR). Inhibition of P-glycoprotein could reverse cancer MDR. Here, we show that schisandrin B, a naturally occurring compound from Schisandra chinensis (Turcz.) Baill, bears strong potency to inhibit P-glycoprotein. Schisandrin B reversed the drug resistance of four MDR cell lines characterized with overexpression of P-glycoprotein and fully restored the intracellular drug accumulation by interacting with P-glycoprotein. Schisandrin B has a core structure of dibenzocyclooctadiene, representing a novel P-glycoprotein inhibitor. To our best knowledge, the role of schisandrin B to inhibit P-glycoprotein has not been reported.

Topics: Affinity Labels; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azides; Cell Line, Tumor; Cell Proliferation; Cyclooctanes; Daunorubicin; Dihydropyridines; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Humans; Inhibitory Concentration 50; K562 Cells; Lignans; Models, Chemical; Neoplasms; Polycyclic Compounds; Protein Binding; Tetrazolium Salts; Thiazoles; Time Factors

Recent data suggest that expression of the membrane P170-glycoprotein (P-gp) may confer resistance to the topoisomerase-I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 microM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Dihydropyridines; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Neoplasms; Phenotype; Topotecan; Tumor Cells, Cultured

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Humans; Neoplasms; Risk Factors

Newly synthesized 1,4-dihydropyridine derivatives had been screened to determine whether they could overcome vincristine (VCR)-resistance in VCR-resistant (P388/VCR) leukemia-bearing mice, and six compounds had strong reversing ability among the screened compounds. We further determined whether NK-250 and NK-252 among the six compounds could potentiate cytocidal activities of etoposide (VP16) as well as VCR against both multidrug-resistant (MDR) cell line (VJ-300) and atypical MDR cell line (KB/VM-4). Both VJ-300 and KB/VM-4 were derived from the same parental human cancer KB cell line: VJ-300 cells showed enhanced expression of a MDR-specific glycoprotein of molecular weight of 170,000 Da (gp170) while KB/VM-4 cells were selected as teniposide (VM26)-resistant cell line with no expression of gp170. NK-250 and NK-252 potentiated the cytotoxic action of VCR about 2- to 10-fold against KB and KB/VM-4 cells, and they almost completely reversed VCR-resistance in VJ-300 cells. By contrast, NK-250 and NK-252 potentiated the cytotoxic action of VP16 about 2-fold against KB cells while they reversed 5- to 10-fold VP16-resistance in both VJ-300 and KB/VM-4 cells. The reversal effect by NK-250 and NK-252 of VCR-resistance in VJ-300 cells appeared to be due to enhanced cellular accumulation of radioactive VCR through interaction to 170-kDa P-glycoprotein. The potentiation effects by these dihydropyridines of VCR and VP16 on KB or KB/VM-4 cells also appeared to be due to enhanced accumulation of radioactive VP16 or VCR, but the effects might be mediated through other mechanisms, plausibly enhanced cellular uptake of the drugs.

Topics: Antineoplastic Agents; Cell Survival; Dihydropyridines; Dioxins; Drug Resistance; Drug Synergism; Etoposide; Humans; Intracellular Fluid; Neoplasms; Tritium; Tumor Cells, Cultured; Vincristine

Multidrug-resistance is frequently characterized by enhanced drug efflux resulting from a membrane glycoprotein of 170,000 daltons (P-glycoprotein). Analysis of cloned cDNAs for the human MDR 1 gene, whose product is the P-glycoprotein, indicates that P-glycoprotein is an energy-dependent drug-efflux system for cytotoxic hydrophobic anticancer drugs. We have demonstrated that a photoanalog of a reversing agent, SDB-ethylenediamine, specifically binds to P-glycoprotein. The binding site on P-glycoprotein seems to be identical with that of anticancer agents and other reversing agents. On the other hand, the radioactive photoactive dihydropyridine calcium channel blocker, [3H] azidopine, photolabels P-glycoprotein in membrane vesicles from multidrug-resistant cells. This photolabeling is almost completely inhibited by excess dihydropyridine analogs that reverse or lower drug-resistance. In contrast, the labeling is not significantly inhibited by analogs that do not reverse resistance. These results suggest that it may be possible to quickly screen for dihydropyridine analogs that reverse multidrug resistance by measuring the inhibition of [3H] azidopine labeling of P-glycoprotein.

Topics: Affinity Labels; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azides; Dihydropyridines; Drug Resistance; Humans; In Vitro Techniques; Membrane Glycoproteins; Neoplasms