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PubMed2002

Poly(L-glutamic acid)--anticancer drug conjugates.

Chemotherapy has had limited success in the treatment of cancer over the years, due, in part, to the untoward toxicity of the therapeutic agent to normal cells. The design of tailor-made polymer conjugates provides a synthetic approach that can overcome some of the problems. Several synthetic polymer-based anticancer drug conjugates have entered clinical studies. This report reviews the chemistry, physicochemical properties, and therapeutic applications in cancer therapy of polymeric chemotherapeutic agents based on poly(L-glutamic acid). Targeted delivery of anticancer agents using poly(L-glutamic acid) as the drug carrier is also discussed with emphasis on the design of innovative polymeric constructs.

Anthracyclines↗

PubMed2000

Monitoring pharmacokinetics of anticancer drugs: non-invasive investigation using magnetic resonance spectroscopy.

Magnetic resonance spectroscopy (MRS) offers the unique advantage of detecting, identifying and quantifying chemicals deep within the living body in a totally non-invasive manner. In studies on pharmacology and toxicology of anticancer drugs, MRS and the closely related technique magnetic resonance imaging (MRI) have many uses. MRS in particular, despite its low sensitivity, offers unique insights into pharmacokinetics (the changing concentration of the drug at its site of action) which can be monitored, and metabolism (both activation and detoxification) can be detected in real time. This review considers some recent work on (19)F, (31)P, (1)H and (13)C MRS of anticancer drugs. Future possibilities for (13)C MRS and (1)H MRS studies of drugs and their metabolites are considered in detail.

Antineoplastic Agents↗

PubMed2001

Interaction between novel anticancer agents and radiation in non-small cell lung cancer cell lines.

Integration of chemotherapy and radiation is the standard practice in the management of locally advanced inoperable NSCLC. To assess the biological interaction between third generation chemotherapeutic agents and radiation in non-small cell lung cancer (NSCLC) in vitro, we tested a number of different drugs (paclitaxel, docetaxel, gemcitabine, topotecan, SN-38 and cisplatin) combined with radiation, in lung cancer cell lines. Cellular chemosensitivity was determined, using the semi-automated colorimetric MTT assay, after 48, 72 and 96 h of exposure to increasing drug concentrations, (0.001-100 microM) and radiation doses (100-400 cGy). Cell lines used were the adenocarcinoma (ADK), A-549, and the squamous-cell carcinoma (SCC), LX-1. Cells were pre-treated with anticancer agents at 24, 12 and 0 h before irradiation. Cytofluorimetric cell cycle analysis was performed. A significant S-phase block or a G(2)/M block was seen with gemcitabine and topotecan or paclitaxel pre-treatment, respectively. Apoptosis was seen only after paclitaxel exposure in the A-549 cell line. Despite a similar pattern of cell-kinetic changes induced by chemotherapy pre-treatment in all cell lines, the adenocarcinoma A-549 cell line was not radiosensitized by any of the anticancer agents tested, whereas synergism was observed in the LX-1 squamous carcinoma cell line, when exposed to gemcitabine, SN-38, topotecan and cisplatin. Paclitaxel, despite a favourable cell cycle effect, was not found to be synergistic with radiotherapy in our experimental model. In conclusion, the observed synergism appears to be dose- and timing-independent and seems to be related to the histological subtype being present in SCC only. Favourable perturbation of the cell cycle is evident with all the new agents tested in both cell types, but was not sufficient to produce synergism with radiation.

Antineoplastic Agents↗

PubMed2003

In vitro effects of combinations of cis-amminedichloro (2-methylpyridine) platinum (II) (ZD0473) with other novel anticancer drugs on the growth of SBC-3, a human small cell lung cancer cell line.

Among numerous clinical regimens of combination chemotherapy, synergy has been observed to be particularly marked with combinations containing cisplatin (CDDP). However, the clinical use of CDDP has sometimes been limited by acquired resistance. The new-generation platinum drug, ZD0473, was synthesized with the aim of hindering the reaction of the drug with thiols, by the introduction of a 2-methylpyridine ligand. This enables the drug to exert antitumor activity against cisplatin-resistant cancer cells with elevated glutathione and/or metallothionein levels. The drug was also shown experimentally to overcome cisplatin resistance due to impaired drug accumulation, and enhanced DNA repair/tolerance to platinum-DNA adducts. We investigated the effects of combinations of ZD0473 with other anticancer drugs on the growth of a human small-cell lung cancer cell line (SBC-3). Six novel anticancer drugs were tested: docetaxel (TXT), paclitaxel (TXL), vinorelbine (VNB), irinotecan (CPT-11), gemcitabine (GEM) and pemetrexed (MTA). The growth inhibitory effect of the drugs was measured by MTT assay and the effects of the combination regimens were evaluated by the combination index analysis method developed by Chou and Talalay. Synergy was demonstrated for the combination regimens of ZD0473-GEM and ZD0473-TXL, while an additive effect was observed with combinations containing TXT, VNB, CPT-11 or MTA. In the case of the ZD0473-GEM combination, synergy was observed over a wide range of inhibition levels at dose ratios of 50:1, 100:1 and 250:1. The level of synergy was equivalent to that observed for combinations of CDDP-etoposide, CDDP-GEM and nedaplatin-CPT-11. The results suggest that the combination of ZD0473 with GEM merits further investigation in small cell lung cancer.

Antimetabolites, Antineoplastic↗

PubMed2000

Anticancer drugs plus cytokines: immunodulation based therapies of mouse tumors.

As demonstrated in this laboratory, several cytotoxic anticancer agents have immunomodulating effects at relatively low doses and, in combination with non-toxic doses of certain cytokines, can exert immunity-dependent curative effects in mouse tumor models. Thus, adriamycin (Dox) has been shown to enhance the activation of macrophages with associated increases of IL1 and TNF production, to stimulate the production of IL2 and the development and action of CTLs. In the EL4 lymphoma C57BL/6 mouse model, combinations of appropriate regimens of Dox plus IL2 or TNF induce cures and the long-term survivors exhibit life-long immunological memory. Combinations of cyclophosphamide plus TNF have analogous effects. In the E0771 breast tumor C57BL/6 mouse model, Dox plus TNF at doses which are without antitumor activity when given alone, cause complete cures of established tumors with concomitant stimulation of CTL and NK cells responses. The mechanisms involved in these therapeutic responses are discussed. In conclusion, the results obtained substantiate the possibility of establishing antitumor curative combination regimens based on the utilization of low non-toxic immunomodulating doses of certain anticancer drugs and specific cytokines.

Adjuvants, Immunologic↗

PubMed2000

Phase II clinical trial design for noncytotoxic anticancer agents for which time to disease progression is the primary endpoint.

Phase II evaluation is a critical screening step in the development of new cancer treatments. Historically, anticancer agents have been cytotoxic; they kill existing cells. As such, the primary endpoint for phase II evaluation has been tumor response rate, the percentage of patients whose tumors shrink > 50%. Biotechnology has led to promising new anticancer agents that are cytostatic. In contrast to cytotoxics, these agents modulate tumor environments and/or cellular targets and are expected to delay tumor growth. Phase II evaluation of such agents may instead focus on failure-time endpoints, such as time to disease progression. We examine a phase II trial design that evaluates clinical benefit by comparing sequentially measured paired failure times within each treated patient. Clinical efficacy is defined by a hazard ratio. Assuming patients eligible for a phase II study of a new cytostatic agent have failed previous cancer treatment, their most recent prior time to progression interval, TTP(1), is uncensored. Time to progression after the cytostatic agent, TTP(2), may or may not be censored at analysis. The design is motivated by a "growth modulation index" (TTP(2)/TTP(1)) and the proposition that a cytostatic agent be considered effective if the index is greater than 1.33. A chi(2) test statistic is employed to evaluate the paired failure-time data (TTP(1), TTP(2)). The degree of correlation between the paired failure times is a key feature of this design. Power of the test was evaluated through simulation of trials. Assuming a null hazard ratio equal to 1.0, a trial designed to detect an alternative hazard ratio equal to 1.3, based on accrual of 25 patients/year for 2 years (50 patients total) and with an additional 2 years of follow-up, has 25%, 46%, and 83% power based on correlations of 0.3, 0.5 and 0.7, respectively. These results demonstrate efficiency of the trial design, given moderate to strong correlations between paired failure times.

Antineoplastic Agents↗

PubMed2002

Synthesis and anticancer and anti-HIV testing of some pyrazino[1,2-a]benzimidazole derivatives.

In this study, some 1-methylene-2,3-diaryl-1,2-dihydropyrazino[1,2-a]benzimidazole and some 1-(2-arylvinyl)-3-arylpyrazino[1,2-a]benzimidazole derivatives were synthesised. The structure elucidation of the compounds was performed by IR, 1H-NMR and MASS spectroscopic data and elemental analyses results. Anticancer and anti-HIV activities of the compounds were examined, however no anti-HIV activity was seen; highly notable anticancer activity was obtained. It was also observed that the compounds were more potent against leukaemia cell lines.

Anti-HIV Agents↗

PubMed2002

New bis-aminomercaptotriazoles and bis-triazolothiadiazoles as possible anticancer agents.

A series of bis-phenoxyacetic acids 2 were prepared starting from corresponding unsubstituted/substituted 1,4-quinols 1. The fusion of bis-phenoxyacetic acids 2 with thiocarbohydrazide gave the corresponding bis-[4-amino-5-mercapto-1,2,4-triazol-3-yl-methyleneoxy]phenylenes (3) in a one pot reaction. The reaction of bis-triazoles 3 with various reagents afforded N-bridged heterocycles 4-6 in good yields. The newly synthesised compounds were screened for their anticancer activity against a panel of 60 cell lines derived from seven cancer types namely, lung, colon, melanoma, renal, ovarian, CNS and leukemia. Some of the tested compounds showed promising anticancer properties.

Antineoplastic Agents↗

PubMed2002

Synthesis, antiprotozoal and anticancer activity of substituted 2-trifluoromethyl- and 2-pentafluoroethylbenzimidazoles.

The synthesis of several halogenated benzimidazoles substituted in position 2 with trifluoromethyl, pentafluoroethyl and 2-thioethylaminodimethyl group is reported. Antiprotozoal and anticancer activity of series of newly synthesized and previously obtained compounds was studied. All of tested bezimidazoles showed remarkable antiprotozoal activity against Giardia intestinalis, Entamoeba histolytica and Trichomonas vaginalis. Of the studied collection of halogenated benzimidazoles the most anticancer-active was the 5,6-dichloro-2-pentafluoroethyl compound, particularly against breast and prostate cancer cell lines.

Animals↗

PubMed2001

In vitro bioassays for anticancer drug screening: effects of cell concentration and other assay parameters on growth inhibitory activity.

In vitro growth inhibition assays were performed using human cancer cell lines at various concentrations with experimental anticancer drugs such as the cryptophycins and other cytotoxins. The effect of variations in assay parameters on the observed growth inhibition of these anticancer therapeutic agents was determined. The results demonstrated that the observed inhibitory activity of these compounds varied inversely with the cell concentrations used. The observed differences in activity between different cytotoxins were not necessarily proportionate. Thus, the relative activities of two toxins also varied with cell concentration. Furthermore, the sensitivity of these cell lines to the cytostatic purine analog, 6-mercaptopurine (used as a control), varied with cell concentration as well. The activity of this compound was dependent on the medium used for cell growth, yielding good activity in Eagle's minimum essential medium, but not in Ham's F-12 (Kaigin) medium. Moreover, growth inhibition by cryptophycin as well as 6-mercaptopurine was also dependent on the serum concentration in the medium. Finally, the sensitivity of the cancer cell lines to various organic solvents commonly used as drug vehicles for in vitro testing, such as ethanol, dimethylformamide, and dimethylsulfoxide, was likewise found to vary inversely with cell concentration.

Antineoplastic Agents↗

PubMed2002

Antitumor efficacy of conventional anticancer drugs is enhanced by the vascular targeting agent ZD6126.

PURPOSE: The present report reviews the preclinical data on combined chemotherapy/vascular targeting agent treatments. Basic principles are illustrated in studies evaluating the antitumor efficacy of the vascular targeting agent ZD6126 (N-acetylcochinol-O-phosphate) when combined with the anticancer drug cisplatin in experimental rodent (KHT sarcoma) and human renal (Caki-1) tumor models. METHODS AND MATERIALS: C3H/HeJ and NCR/nu-nu mice bearing i.m. tumors were injected i.p. with ZD6126 (0-150 mg/kg) or cisplatin (0-20 mg/kg) either alone or in combination. Tumor response to treatment was assessed by clonogenic cell survival. RESULTS: Treatment with ZD6126 was found to damage existing neovasculature, leading to a rapid vascular shutdown. Histologic evaluation showed dose-dependent morphologic damage of tumor cells within a few hours after drug exposure, followed by extensive central tumor necrosis and neoplastic cell death as a result of prolonged ischemia. ZD6126 doses that led to pathophysiologic effects also enhanced the tumor cell killing of cisplatin when administered either 24 h before or 1-24 h after chemotherapy. In both tumor models, the administration of a 150 mg/kg dose of ZD6126 1 h after a range of doses of cisplatin resulted in an increase in tumor cell kill 10-500-fold greater than that seen with chemotherapy alone. In contrast, the inclusion of the antivascular agent did not increase bone marrow stem cell toxicity associated with this anticancer drug. CONCLUSION: The results obtained in the KHT and Caki-1 tumor models indicate that ZD6126 effectively enhanced the antitumor effects of cisplatin therapy. These findings are representative of the marked enhancements generally observed when vascular targeting agents are combined with chemotherapy in solid tumor therapy.

Angiogenesis Inhibitors↗

PubMed2000

Enhancing effect of electric stimulation on cytotoxicity of anticancer agents against rat and human glioma cells.

Electropermeabilization, or electroporation, has been used to deliver genes or drugs into the cytoplasm through micropores in the cell membrane caused by electric stimulation. The cytotoxic effect of a combination of anticancer agents with electric stimulation on rat C6 and human T98G glioma cells was examined in vitro. Electric pulses of 100 microsec square waves (eight cycles at 1 Hz) at various electric fields were delivered to C6 or T98G glioma cell suspensions in combination with several anticancer agents. Cell growth was evaluated 48-72 h after treatment. Measurement of cell lysis by electric stimulation was used to assess the optimum field strength for electroporation. Electric stimulation enhanced significantly the cytotoxicity of bleomycin to both C6 and T98G cells by more than 1000-fold using an electric field of 1750 V/cm for C6 cells and 1000 V/cm for T98G cells. The enhancement disappeared when bleomycin concentration was reduced to 100 pg/ml. The cytotoxicity of carboplatin was weakly but significantly enhanced by electric stimulation when a high dose of carboplatin was used. However, there was no enhancement of the cytotoxicity of nimustine hydrochloride (ACNU), etoposide, and vincristine. These results indicate that the combination of bleomycin and electroporation is the most potent candidate for electrochemotherapy in vivo.

Animals↗

PubMed2001

Chromatographic techniques for the determination of putative dietary anticancer compounds in biological fluids.

Although a great number of papers demonstrate an association between high intake of fruits and vegetables and reduced risk of certain types of cancer, the epidemiological evidence is not conclusive. The identification and quantification of specific dietary anticancer compounds in plasma, urine and tissues is an important aspect of this research. We surveyed the recent literature for original papers which involved the use of separation techniques for the detection and quantification in biological fluids and tissues of putative anticancer compounds which are present in the diet. The compounds included in this review are flavonoids, phytoestrogens, carotenoids, retinoids, vitamin E and ascorbic acid. The review covers papers published in the last 3 years. For each class of compounds we discuss the sample preparation, chromatographic conditions, and validation of the methods used, in order to identify current trends in the bioanalysis of each class of these substances.

Anticarcinogenic Agents↗

PubMed1996

Reversed-phase high-performance liquid chromatography method for the simultaneous quantitation of the lactone and carboxylate forms of the novel natural product anticancer agent 10-hydroxycamptothecin in biological fluids and tissues.

Camptothecins are indole alkaloids isolated from a Chinese tree, Camptotheca acuminata, and have a wide spectrum of anticancer activity in vitro and in vivo. A novel camptothecin congener 10-hydroxycamptothecin (HCPT) has been shown to be more active and less toxic than camptothecin, and the lactone HCPT is believed to be responsible for its anticancer activity. In the present study, a reversed-phase high-performance liquid chromatography, (HPLC) with fluorescence detection was developed and validated for the simultaneous analysis of HCPT for lactone from (I) and carboxylate form (II) in plasma, urine and feces and tissues. Biological samples were prepared by a liquid-liquid extraction method using ice-cold methanol-acetonitrile (1:1, v/v). This method was shown to be reproducible and reliable, with intra- and inter-day variations being less than 7%, and accuracy being 94.3%-102.7%. The limits of determination were 2 ng/ml, 2 ng/ml, 2 ng/g, and 10 ng/ml for HCPT forms I and II in rat plasma, urine, feces, and tissues, respectively. The assay was liner over the range 2-2000 ng/ml (r = 0.999, P < 0.001) with recoveries of greater than 90% for plasma and urine and approximately 70-80% for feces and tissue homogenates through the extraction procedure. This analytic procedure has been successfully applied to a pharmacokinetic study of HCPT in experimental animals and should be useful in the future human studies.

Animals↗

PubMed2003

Oxidation of anthracycline anticancer agents by the peroxidase mimic microperoxidase 11 and hydrogen peroxide.

The interaction of two clinically important anticancer agents doxorubicin (DXR) and daunorubicin (DNR) and the DNR analog 5-iminodaunorubicin (5IDNR) with the model mammalian peroxidase microperoxidase 11 (MP11) and H(2)O(2) has been investigated using spectrophotometric and EPR techniques. We demonstrate that DNR, DXR, and 5IDNR undergo irreversible oxidation by MP11/H(2)O(2), forming colorless products in both phosphate buffer pH 7.0 and in phosphate buffer pH 7.0/MeOH mixture (1:1 vol/vol), suggesting an extensive modification of the compounds' chromophores. The initial rate of the anthracyclines' oxidation is independent of anthracycline concentrations, but is linearly dependent on [H(2)O(2)](i) at constant [MP11](i) (and vice versa), indicating that the reaction is zero order in [anthracycline], first order with respect to [H(2)O(2)] and [MP11], and second order overall. Based on data obtained using DNR, DXR, 5IDNR, and p-hydroquinone k(2app), the apparent second order rate constant for the formation of a reactive intermediate from MP11 and H(2)O(2) (an analog of peroxidase compound I) has been determined to be in the range of (2.51-5.11) x 10(3) M(-1) s(-1) in both solvent systems. EPR studies show that oxidation of DNR, DXR, or 5IDNR with MP11/H(2)O(2) generates free radicals, suggesting that the reaction may be a one-electron process. This study also shows that 5IDNR, but not DNR or DXR, efficiently protects MP11 heme against degradation by H(2)O(2). Our overall conclusion is that MP11 is an effective catalyst of oxidation of anthracyclines by H(2)O(2). Given that, at sites of inflammation or cancer, the anthracyclines can colocalize with peroxidases, protein degradation products, and with H(2)O(2), peroxidation could be one possible fate of these anticancer agents in vivo.

Animals↗

PubMed2002

[Statutory pediatric informations available for anticancer drugs: inventory and proposals].

UNLABELLED: Paediatric medicines are often prescribed off label because appropriate clinical and pharmacological studies have not been conducted in children. A European directive is being written to promote the development of paediatric medicines through incentives to pharmaceutical companies, as is already the case in the US. METHOD: In order to evaluate the status of anticancer drugs, we analyzed the paediatric information available in the Vidal 2000 dictionary for cytotoxic chemotherapy. RESULTS: Among the 76 products, 48 were currently used to treat children with cancer. An indication for paediatric use was described in only 29% of them. Paediatric use was mentioned in the posology chapter in 56% of cases, and in the warning or contra-indication chapter in 17% of cases. Ten products (21%) were devoid of paediatric information. DISCUSSION: The paucity of this official paediatric information contrasts with the number of clinical and pharmacological studies that have been conducted and published by paediatric oncology societies and groups. Indeed, almost 80% of children with cancer are treated using prospective therapeutic research protocols. In conclusion, anticancer medicines have been evaluated in children, but official paediatric information is poor. This situation can be significantly improved with the literature currently available. On the other hand, prospective clinical studies are needed to better define the optimal dose in children under one year of age, to evaluate long-term sequelae in cured patients and to provide appropriate galenic forms for oral chemotherapy. CONCLUSION: Incentives are urgently needed to facilitate access to therapeutic innovations in oncology and their development in children with cancer.

Adult↗

PubMed2000

HPMA copolymer-anticancer drug conjugates: design, activity, and mechanism of action.

The design, synthesis and properties of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers as carriers of anticancer drugs are reviewed. Macromolecular therapeutics based on HPMA copolymers are biocompatible, preferentially accumulate in tumors, and possess a higher anticancer efficacy than low molecular weight drugs. Novel designs of HPMA copolymer carriers resulted in long-circulating conjugates and gene and oligonucleotide delivery systems. HPMA copolymer based macromolecular therapeutics were active against numerous cancer models and are in clinical trials. The data obtained indicated that macromolecular therapeutics activated different signaling pathways and possessed a different mechanism of action than free drugs. This bodes well for the success of future research aimed at identification of new intracellular molecular targets as a basis for the design of the second generation of macromolecular therapeutics.

Animals↗

PubMed2000

Attenuation of telomerase activity does not increase sensitivity of human melanoma cells to anticancer agents.

In tumour cells, replicative immortality is attained through stabilisation of telomeres by telomerase. Recent evidence suggests that telomerase plays an anti-apoptotic role. Since apoptosis is the primary mode of cell death induced by several drugs, telomerase could be involved in determining the chemosensitivity profile of tumour cells. We investigated whether inhibition of telomerase activity through a hammerhead ribozyme targeting the RNA template of telomerase influences the susceptibility of human melanoma cells to a variety of anticancer agents (platinum compounds, taxanes, topoisomerase I inhibitors). The ribozyme sequence was inserted into an expression vector and the JR8 human melanoma cell line was transfected with it. The cell clones obtained showed a reduced telomerase activity. Growth inhibition curves generated after exposure of ribozyme-transfectant clones to individual drugs were superimposable to those obtained from parental cells. Moreover, telomerase inhibition did not promote apoptosis as a cellular response to drug treatment. Overall, our results indicate that downregulation of telomerase activity does not increase the sensitivity of melanoma cells to anticancer drugs.

Antineoplastic Agents↗