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PubMed2006

Synthesis and biological evaluation of aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F structurally related to the amaryllidaceae anticancer constituents.

Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, l-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds.

Amaryllidaceae Alkaloids↗

PubMed2006

Stille coupling reactions in the synthesis of hypoxia-selective 3-alkyl-1,2,4-benzotriazine 1,4-dioxide anticancer agents.

The introduction of a 3-alkyl substituent is a key step in the synthesis of 1,2,4-benzotriazine 1,4-dioxide hypoxia-selective anticancer agents, such as SN29751. The Stille reaction of 3-chloro-1,2,4-benzotriazine 1-oxides (BTOs) 5 was inhibited by the presence of electron donating substituents on the benzo ring, thus limiting the range of compounds available for SAR studies. The use of 3-iodo-BTOs 8 did not provide a significant improvement in the yields of 3-ethyl-BTOs 6. Microwave-assisted Stille coupling of chlorides 5 gave dramatically improved yields, which were consistently superior to those from the corresponding iodides 8. The application of microwave-assisted synthesis extended the range of substituted BTOs available for SAR studies and provided an efficient, scalable synthesis of the investigational anticancer agent, SN29751 (1).

Antineoplastic Agents↗

PubMed2005

Hydrolysis process of the second generation platinum-based anticancer drug cis-amminedichlorocyclohexylamineplatinum(II).

The hydrolysis process of the anticancer drug cis-amminedichlorocyclohexylamineplatinum(II) (JM118 or cis-[PtCl2(NH3)cyclohexylamine]) and the influence of solvent models therein have been studied using hybrid density functional theory (B3LYP). The aquation reactions leading to the activated drug forms a key step for the reaction with the target DNA. In this study, the stepwise hydrolysis, cis-[PtCl2(NH3)cyclohexylamine] + 2 H2O --> cis-[Pt(NH3)cyclohexylamine(OH2)2]2+ + 2 Cl- was explored, using three different models. Implicit solvent effects were incorporated through polarized continuum models. The stationary points on the potential energy surfaces for the first and second hydrolysis steps, proceeding via a general S(N)2 pathway, were fully optimized and characterized. It was found that the explicit solvent effects originating from the inclusion of extra water molecules into the system are significantly stronger than those arising from the bulk aqueous medium, especially for the second aquation step, emphasizing the use of appropriate models for these types of problems. In comparison with previous work on the parent compound cisplatin, a slower rate of hydrolysis is determined for the first (rate determining) reaction. The results furthermore imply that the doubly aquated form of JM118 will be the main DNA binding form of the drug. The results provide detailed energy profiles for the mechanism of hydrolysis of JM118, which may assist in understanding the reaction mechanism of the drug with the DNA target and in the design of novel Pt-containing anticancer drugs.

Antineoplastic Agents↗

PubMedDate not supplied

Exploratory chemoinformatic analysis of cell type-selective anticancer drug targeting.

In pharmaceutical development, structure-activity relationship studies aim to identify characteristics of chemical structures associated with well-defined activity end points. While this goal-driven approach is ideally suited for lead development purposes, a more exploration-driven approach is needed to discover cell type-selective drug targeting mechanisms in complex data sets. Growth inhibition profiles across different cancer cell lines are potentially informative with respect to molecular mechanisms targeting the activity of anticancer agents to specific tumor cells, yet only a small number of mechanistic associations between chemical structure and growth inhibition profiles have been discovered to date. Here, we have applied an exhaustive statistical analysis strategy to more than 10000 compounds in the NCI's anticancer agent database to identify molecular substructures associated with specific cytotoxicity signatures against a panel of human tumor-derived cancer cell lines (the Developmental Therapeutics Program 60-cell line panel). Some of the most significant substructures conferring cell type-selective cytotoxic activity include a large family of delocalized lipophilic cations; chloropurines, chloropyrimidines, and thiazoles; organosulfur chelators and organometallic complexes; and an unexpectedly related family of alkyl-lysophospholipids and phosphate prodrugs. Information from cell-based assays and gene expression measurements have been related to substructures represented in the chemical space covered by the library, yielding several candidate targeting mechanisms.

Antineoplastic Agents↗

PubMed1998

Down-regulation of transforming growth factor-beta and interleukin-10 secretion from malignant glioma cells by cytokines and anticancer drugs.

The effect of treatment with interleukin-1 beta (IL-1 beta), interferon-gamma (IFN-gamma), vincristine, and etoposide was evaluated on the secretion of transforming growth factor-beta (TGF-beta) and IL-10 and the expression of major histocompatibility complex (MHC) class I, intercellular adhesion molecule-1 (ICAM-1), and CD80 molecules by malignant glioma cells. Five malignant glioma cell lines were treated with IL-1 beta, IFN-gamma, and/or anticancer agents (vincristine and etoposide). Combined treatment with IL-1 beta and IFN-gamma caused greater inhibition of TGF-beta secretion compared to treatment with IFN-gamma, and almost the same levels of inhibition as treatment with vincristine and etoposide. The greatest inhibition of TGF-beta secretion was achieved by treatment with all agents. Low levels of IL-10 secretion were determined in two out of five malignant glioma cell lines. This IL-10 secretion was inhibited by treatment with IL-1 beta, IFN-gamma, vincristine, and/or etoposide. Treatment with both cytokines and anticancer agents increased the expression of MHC class I and ICAM-1 in all tumor cell lines. The mean increase of expression of MHC class I was 50% and that of ICAM-1 was 12-fold. No tumor cell lines expressed CD80 molecules on the cell surface, and no treatment caused CD80 expression. These results suggest that TGF-beta and IL-10 secretion by malignant glioma cells can be suppressed by treatment with a combination of IL-1 beta, IFN-gamma, vincristine, and etoposide, and the treatment up-regulates MHC class I and ICAM-1 expression on tumor cells. These results have implications for immunotherapy and chemotherapy in patients with malignant tumors.

Antigens, Neoplasm↗

PubMed2000

DNA G-quadruplexes, telomere-specific proteins and telomere-associated enzymes as potential targets for new anticancer drugs.

Telomeres and telomerase have been subjects to a tremendous attention from scientists and oncologists during the past 5 years. This interest has been motivated by the potential of telomerase as a tumor marker for the diagnosis and the prognosis of cancer. The possible use of telomerase or telomeres as new targets for anticancer drugs also triggered investigations. The expression of telomerase was found in overall 85% of cancers. Telomerase is early expressed during oncogenesis with a gradient indicating that a high level of telomerase expression could be associated with a bad prognosis. Therefore, drugs targeting telomerase and telomeres might be useful in many human tumors with little restrictions regarding the tumor type or on the stage of the disease. Moreover, since telomerase is not or slightly expressed in normal cells, it has been postulated that drugs targeting telomerase would induce low toxicity. The race for the discovery of telomerase inhibitors has started while the identification of the components controlling telomerase, telomeres, cell survival, senescence, and apoptosis was still in progress. The recent identification of components regulating telomere length and telomerase expression (TRF1, TRF2, and tankyrase) opened a variety of new opportunities to control telomerase/telomere interactions. Meanwhile, a proof of principle was provided that changing telomere interactions with telomere binding proteins by chemical or biological means can induce cancer cell death. Interestingly, recent data challenge the old paradigm which suggested that a long exposure to telomerase and telomere inhibitors is necessary to induce anticancer effects. In this paper, we review the most recent information concerning the regulation of telomere length and telomerase expression, with emphasis on mechanisms that might translate into new drug discovery.

Animals↗

PubMed2000

Expression of Bcl-2 but not Bax or p53 correlates with in vitro resistance to a series of anticancer drugs in breast carcinoma.

Programmed cell death is an important determinant of the response to chemotherapy. Among the factors controlling this process, a significant role is played by bcl-2, bax and p53. The in vitro chemosensitivity of the 177 breast carcinomas was assessed by the histoculture drug response assay (HDRA) using mitomycin C (MMC), 5-fluorouracil (5-Fu), adriamycin (ADM), cisplatin (CDDP), and cyclophosphamide (CPA). The susceptibility of Bcl-2-negative tumors to all the drugs killing was significantly higher than that of Bcl-2-positive tumors. No relationship between Bax or p53 immunoreactivity and sensitivity for any of anticancer drugs studied was demonstrated. Immunohistochemical results regarding Bcl-2 are promising in the evaluation of the sensitivity of cancer cells to a series of anticancer drugs and might be therapeutically useful as an indicator of response to adjuvant chemotherapy for breast cancer.

Antineoplastic Agents↗

PubMed1998

Proliferation indices as molecular pharmacodynamic endpoints in evaluation of anticancer drug effect in human solid tumors.

PURPOSE: The present study compared proliferative indices, i.e. incorporation of DNA precursor (i.e. thymidine or TdR, and bromodeoxyuridine or BrdU) and expression of proliferating cell nuclear antigen (PCNA), as molecular pharmacodynamic endpoints in evaluation of anticancer drug effect in human solid tumors. METHODS: Tumor specimens obtained from patients were grown as histocultures. After treatment with doxorubicin, mitomycin C, and/or paclitaxel, cells labeled by [3H]TdR were identified using autoradiography, and cells labeled by BrdU and PCNA were identified using immunohistochemical techniques. Drug effect was measured as reduction of DNA precursor-labeled cells or PCNA-expressing cells. RESULTS: The results indicate that (a) the two DNA precursors, TdR and BrdU, labeled the same cells and resulted in identical pharmacodynamics, (b) the pharmacodynamics established using inhibition of DNA precursor incorporation were qualitatively and quantitatively different from the pharmacodynamics established using inhibition of PCNA expression, (c) the inhibition of PCNA expression was erratic in some tumors, and (d) the differences in pharmacodynamics established using the two end points are drug-specific, with greater differences for paclitaxel than for mitomycin C. CONCLUSIONS: The erratic results measured by the PCNA labeling method suggest that this method may be less reliable than the conventional DNA precursor labeling method. The finding of identical pharmacodynamics of doxorubicin and paclitaxel established using BrdU and [3H]TdR indicates that the two precursors are interchangeable. Because the methodology for detecting BrdU incorporation requires less time and does not require the use of radioactivity, we conclude that inhibition of BrdU incorporation represents a useful endpoint for evaluating the antiproliferative activity of anticancer drugs in human solid tumors.

Antineoplastic Agents↗

PubMed2002

Lack of in vitro-in vivo correlation of a novel investigational anticancer agent, SH 30.

In solid tumors, the reasons for the lack of in vitro and in vivo correlation of drug activities are multifold and includes permeability to the tumor cells, interstitial hypertension and metabolic degradation. So, it is important to study the permeability and metabolic disposition of new compounds early in discovery and development of anticancer drugs. An experimental anti-cancer drug, SH 30 demonstrated highly selective and potent cytotoxic activity against a number of multi-drug resistant tumor cell lines in vitro. However, it was inactive in a murine tumor model. This study was conducted to identify the barriers that result in lack of correlation between in vitro and in vivo cytotoxic activity of novel anticancer agents. Two important barriers: physical (permeability) and metabolic (enzymatic inactivation) to poor delivery of SH 30 to solid tumors were investigated in this study. Tumors were sliced to separate the vascular and avascular sections. The concentrations of the drug at various regions of the tumor after single and multiple doses were investigated to determine the permeability barrier. The permeability barrier was also probed using two in vitro model systems, namely, matrigel films representing extracellular matrix and caco-2 multilayer cell cultures that simulate solid tumors. The drug and its metabolite concentrations were determined in the plasma and tumors to determine the metabolic barrier to the drug cytotoxic action. The metabolic barrier was further probed using in vitro mouse hepatocytes and liver microsome preparations. Our examination revealed the metabolic barrier to be the major contributor to the ineffectiveness of SH 30 in vivo. Examination of concentration of the drug across various regions of the tumor corroborated by data from in vitro permeation studies suggested that, for SH 30, permeability barrier did not exist. After single injection, the concentrations of SH 30 and its metabolites in plasma and tumor were comparable to another investigational drug with similar features (XK 469). Contrary to day 1, after 8 consecutive days of administration, SH 30 concentrations were significantly lower, while the metabolites concentrations were higher, suggesting extensive metabolism due to induction of enzyme(s). The in vitro hepatocytes and liver microsome results also showed SH 30 biotransformation to the same metabolites. Neither drug penetration, nor drug distribution into regions of the tumors distal to vasculature were impeded. The inactivity of SH 30 in vivo is primarily due to induction of extensive metabolism to inactive metabolites. This metabolism prevents adequate drug levels being achieved in the tumor.

Administration, Oral↗

PubMed1992

Optimized formulation of magnetic chitosan microspheres containing the anticancer agent, oxantrazole.

A combined emulsion/polymer cross-linking/solvent evaporation technique was used to prepare magnetic chitosan microspheres (MCM) containing the anticancer drug, oxantrazole. A central composite experimental design was used to simultaneously evaluate a variety of formulation factors on a number of response variables, such as the percentage of oxantrazole entrapped in the MCM. In association with the study design, statistical optimization procedures indicated the factors that significantly influence MCM preparation and what levels of the factors are needed to produce optimum MCM. Entrapment of anticancer agents into biodegradable microspheres is difficult because of low aqueous drug solubility and porosity of the particles. The latter effect was circumvented by a chitosan cross-linking step that resulted in approximately 3% (w/w) oxantrazole entrapment in the MCM via the optimization procedures. The combined formulation and statistical optimization strategy provide a basis to develop other microparticulate systems and led to a dosage form that can be used for future in vivo investigations.

Anthraquinones↗

PubMed1995

The use of intracerebral microdialysis for the determination of pharmacokinetic profiles of anticancer drugs in tumor-bearing rat brain.

PURPOSE: The use of intracerebral microdialysis as a tool to measure the penetration of anticancer agents in brain tumor was investigated. METHODS: Following intravenous (iv) administration of 75 mg/kg. concentration-time profiles of methotrexate (MTX) were determined in brain cortical dialysate and in plasma. The individual ratio of the area under the curve of MTX in brain dialysate over that in plasma (MTX penetration) was determined in normal brain, in tumor-bearing brain and in brain after sham tumor implantation. Individual brains were examined histologically on the presence of tumor, as well as for other factors that might influence local MTX penetration. Histological scores were related to the individual data on penetration of MTX. RESULTS: MTX penetration values were higher in cortical brain at the site of the tumor, as compared to the levels measured in normal or sham implanted brain (mean increase to 250%). In the cortical brain contralateral to the tumor, MTX penetration values were found to be lower than in normal brain (mean reduction of 65%). Furthermore, it appeared that in the absence of tumor tissue, the presence of exudate around the probe was independently associated with increased penetration of MTX into the brain. CONCLUSIONS: Tumor tissue appeared to be the most important parameter in changing local MTX penetration in brain after tumor implantation. In general, it is anticipated that intracerebral microdialysis combined with histological examination can be used to investigate effects of brain tumor presence on regional (periprobe) penetration of anticancer drugs into the brain.

Animals↗

PubMed2002

Transport characteristics of L-carnosine and the anticancer derivative 4-toluenesulfonylureido-carnosine in a human epithelial cell line.

PURPOSE: The aim of the present study was to evaluate whether the transepithelial transport of the anticancer compound 4-toluenesulfonylureido-carnosine (Ts-carnosine) and the dipeptide moiety L-carnosine was due to a hPepT1 carrier-mediated flux. METHODS: Transport experiments were conducted using Caco-2 cell monolayers and either reversed-phase HPLC-UV or liquid scintillation counting methods for quantification. pKa, LogD, and LogP were determined using the Sirius GlpKa meter. RESULTS: L-carnosine was transported across the apical membrane with a Km,app of 2.48 +/- 1.16 mM and a Vmax of 2.08 +/- 0.34 nmol x cm(-2) x min(-1) and across the basolateral membrane with a Km,app of 7.21 +/- 3.17 mM and a Vmax of 0.54 +/- 0.10 nmol x cm(-2) x min(-1), and transepithelially with a Papp of 4.46 x 10(-2) +/- 6.4 x 10(-6) cm x min(-10). Ts-carnosine had an affinity (Ki) for hPepT1 of 2.33 +/- 0.54 mM; however, the transepithelial transport was low as compared to that of L-carnosine. CONCLUSIONS: L-carnosine was transported across both the apical and basolateral membrane of Caco-2 cell monolayers in a carrier-mediated manner however, the transepithelial transport followed apparent simple non-saturable kinetics. Ts-carnosine had an affinity for hPepT1 but a relatively low transepithelial transport. This indicates that the transepithelial transport of L-carnosine and Ts-carnosine is not hPepT1 carrier-mediated and that L-carnosine is not a suitable dipeptide moiety for hPepT1-mediated absorption of sulfonamide-type anticancer compounds.

Antineoplastic Agents↗

PubMed2002

Multiple-pool cell lifespan model of hematologic effects of anticancer agents.

The leukopenic effects of anticancer agents are described using a semi-physiologic multiple-pool cell lifespan model. The time course of myelosuppression in relation to the drug concentration vs. time profile was characterized using a three pool indirect model. The proliferation and maturation stages of myeloid cells in the bone marrow and cell removal from the circulation were quantitated with a cell life-span concept. Drug effects were assumed to take place in the bone marrow based on irreversible linear or capacity-limited cytotoxicity. Mathematical derivations and computer simulations (Adapt II) were used to examine the properties of the model. Data from the literature were also analyzed. Cell response profiles after therapy typically exhibit a lag period, reduction to a nadir, and return to baseline. The predicted values of the time periods of granulopoiesis were 10-14 days for proliferation, and 1-6 days for maturation of progenitor cells in the bone marrow. The proposed irreversible mechanism of cell killing by anticancer drugs explains previously observed relationships between leukocyte nadir counts and exposure to the drug and/or duration of drug concentrations above some threshold level. The model was applied to literature data for paclitaxel and etoposide effects on leukocyte counts. The predicted value of KC50 for paclitaxel ranged from 0.004 to 0.2 microgram/mL and for etoposide 2 micrograms/mL. The present model accounts for drug-induced leukopenia using a physiologic cell production and loss model and irreversible cytotoxicity in a precursor pool.

Animals↗

PubMed2003

Clinical gene therapy for brain tumors. Liposomal delivery of anticancer molecule to glioma.

Liposomes are one of the most promising delivery systems for genes, proteins, and other biological molecules and they are expected to become a new therapeutic tool for the treatment of brain tumors, especially malignant gliomas. Until now, transfer of anticancer molecules using liposomes has been studied by a lot of investigators and it has been found to induce regression of experimental gliomas, resulting in establishing some original and effective therapies. Gene therapy using cationic liposomes is also one of them. Here we introduce the advanced medicine for brain tumors using liposomes containing some anticancer molecules (for example, gene, antibody, antisense, or magnetite), based on our basic and clinical research.

Adult↗

PubMed1980

Interaction of human serum albumin with anticancer agents in vitro.

The influence of human serum albumin (HA) on the biological effects of 13 chemotherapeutic agents was studied in vitro in the human leukaemia cell line MOLT-3. On the basis of changes in biological activity influenced by HA, these drugs may be divided into three types. Type I agents include cis-diamminedichloroplatinum (II), 4'-(9-acridinylamino)methanesulphon-m-anisidide, neocarzinostatin, nitrogen mustard, adriamycin, daunorubicin and mitomycin C--drugs whose biological activities are reduced in the presence of HA. The biological activities of Type II drugs (cytosine arabinoside, fluorouracil and actinomycin D) are not influenced by HA. The biological activities of Type III drugs (bleomycin, vincristine and vinblastine) are increased in the presence of HA. These results indicate that serum HA interferes in vitro with certain anticancer agents in terms of biological activity and, probably, clinical effectiveness. HA-drug interaction may be a major factor governing the pharmacology of Type I anticancer agents in man.

Animals↗

PubMed1992

The effects of ICRF-154 in combination with other anticancer agents in vitro.

We studied the effects of ICRF-154 in combination with 11 anticancer agents on four human leukaemia cell lines. Cells were incubated for 3 days in the presence of two drugs (ICRF-154 and one other), and cell growth inhibition was determined by MTT assay. Effects of drug combinations at the ID50 level were analysed using the isobologram method (Steel). In the lymphoblastic leukaemia cell lines, MOLT-3, HSB, and B-ALL, supra-additive effects were observed for ICRF-154 in combination with amsacrine, bleomycin, doxorubicin, and etoposide. Additive effects were observed for its combinations with cisplatin, CPT-11, cytosine arabinoside, 5-fluorouracil, mitomycin C, and vincristine. Sub-additive to protective effects were observed in combination with methotrexate. In an erythroleukaemia cell line, K-562, no drug showed supra-additive effects with ICRF-154, while sub-additive to protective effects were observed for ICRF-154 in combination with cisplatin and methotrexate. The other drugs showed additive effects with ICRF-154. These results indicate that the combined effects of ICRF-154 with other agents vary, depending on the cell line. Against lymphoid malignancies, ICRF-154 would be advantageous when administered simultaneously with many anticancer agents. Of such agents, amsacrine, bleomycin, doxorubicin, and etoposide are the most suitable, while methotrexate is least suitable for such combined treatment.

Antineoplastic Agents↗

PubMed1993

Implantation treatment method of slow release anticancer doxorubicin containing hydroxyapatite (DOX-HAP) complex. A basic study of a new treatment for hepatic cancer.

We performed an experimental study on slow releasing anticancer drug implantation treatment as a new therapy for hepatocellular carcinoma. Hydroxyapatite (HAP) was chosen for the carrier material and doxorubicin hydrochloride (DOX) for anticancer agent. DOX-HAP was produced by adsorbing DOX to porous HAP particles of 1375 +/- 125 microns diameter using the freeze drying method. In vitro experiments showed slow release of the drug resulting in the steady release of DOX from HAP for 1 month duration. In healthy white rabbits with DOX-HAP implantation in the liver, serum DOX was not detectable, and DOX release rate was stable at the implanted region after 7, 14, and 21 days. When DOX-HAP (DOX; 100 mg kg-1) was administered to mice with sarcoma 180, an improved survival rate was observed without acute toxicity. We also found that VX2 liver tumour growth on white rabbit was inhibited by implantation of DOX-HAP, without acute toxicity. We hope that DOX-HAP implantation therapy will open up new avenues for the treatment of hepatoma.

Animals↗

PubMed1993

SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours.

SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide, WIN 59075, tirapazamine) is the lead compound in a new class of bioreductive anticancer drugs, the benzotriazine di-N-oxides. It is currently undergoing Phase I clinical testing. The preferential tumour cell killing of SR 4233 is a result of its high specific toxicity to cells at low oxygen tensions. Such hypoxic cells are a common feature of solid tumours, but not normal tissues, and are resistant to cancer therapies including radiation and some anticancer drugs. The killing of these tumour cells by SR 4233, particularly when given on multiple occasions, can increase total tumour cell killing by fractionated irradiation by several orders of magnitude without increasing toxicity to surrounding normal tissues. Topics covered in this review include the rationale for developing a hypoxic cytotoxic agent, the cytotoxicity of SR 4233 as a function of oxygen concentration, the mechanism of action of the drug and its intracellular target and the in vivo evidence that the drug may be useful as an adjunct both to radiotherapy and chemotherapy. Finally, the major unanswered questions on the drug are outlined.

Animals↗