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PubMed2005

Marine natural products as anticancer drugs.

The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.

Animals↗

PubMed2005

Proteome-based identification of molecular markers predicting chemosensitivity to each category of anticancer agents in human gliomas.

To identify the protein markers that are clinically useful for predicting efficacy of anticancer agents, we investigated the correlation between the proteome profiling patterns and the in vitro chemosensitivity in human gliomas. The proteome of 93 surgical samples were analyzed with two-dimensional gel electrophoresis (2DE) and mass spectrometry. The in vitro chemosensitivities to 10 different kinds of anticancer agents (cyclophosphamide, nimustine, cisplatin, cytosine arabinoside, mitomycin C, peplomycin, adriamycin, etoposide, vincristine, paclitaxel) were measured by flow cytometric detection of apoptosis. We identified a set of 41 proteins that significantly affected the in vitro chemosensitivity to each category of anticancer agents. Many of the proteins that correlated with chemoresistance were categorized into the signal transduction proteins including the G-proteins. The present study showed that the proteome analysis using 2DE could provide a list of proteins that may be the potential predictive markers for chemosensitivity in human gliomas. They can also be direct and rational targets for anti-glioma therapy and be used for sensitization to the conventional chemotherapeutic regimens.

Antineoplastic Agents↗

PubMed1992

Resistance to anticancer drugs of well differentiated gastric adenocarcinoma with venous invasion.

A comparison of the chemosensitivity of well-differentiated human gastric cancer tissues was made between histological venous invasion positive (v(+)) and negative (v(-)) tissues, using the succinate dehydrogenase inhibition (SDI) test. These tissues obtained at the time of surgery were exposed to six anticancer drugs: carboquone (CQ), adriamycin (ADM), mitomycin C (MMC), aclacinomycin A (ACR), cisplatin (DDP) and 5-fluorouracil (5-FU). Chemosensitivity was judged to be positive when the succinate dehydrogenase (SD) activity of the drug exposed cells decreased to below 50% of that of control cells. Decrease in the SD activity was more apparent in the v(-) tissues than in the v(+) tissues, exposed to the anticancer drugs and in particular to ADM (P less than 0.01), MMC (P less than 0.02) and DDP (P less than 0.05). The sensitivity rates to all six anticancer drugs were lower in the v(+) tissues. The resistance rates to all drugs tested were 0% in the v(-) tissues, but 21% in the v(+) tissues. In light of these observations, patients with gastric cancer of the well differentiated type and the histological venous invasion, will probably show a less positive response to cancer chemotherapy.

Adenocarcinoma↗

PubMed1992

Effects of mitoxantrone in combination with other anticancer agents on a human leukemia cell line.

To investigate the effects of mitoxantrone in combination with other anticancer agents, a human T-cell leukemia cell line, MOLT-3, was incubated for 3 days in the presence of two drugs (mitoxantrone and the combined drug) and cell growth inhibition was determined by assay with 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazonium bromide. The effects of drug combinations at doses giving 80% inhibition (ID80) were analyzed by an improved isobologram method. A supra-additive (synergistic) effect was observed for mitoxantrone in combination with amsacrine, cisplatin, or cytosine arabinoside. An additive effect was observed for its combination with bleomycin, doxorubicin, etoposide, 5-fluorouracil, mitomycin C, 6-mercaptopurine, or vincristine. A sub-additive (antagonistic) effect was observed for its combination with methotrexate. These data suggest that mitoxantrone, administered simultaneously with any one of a majority of anticancer agents we studied, is advantageous for cytokilling. Of the anticancer agents tested, amsacrine, cisplatin, and cytosine arabinoside are the most suitable for combination with mitoxantrone, and these combinations are worthy of clinical investigation. Methotrexate in our system is inappropriate for simultaneous administration with mitoxantrone. These data should provide useful information for the establishment of clinical protocols involving mitoxantrone.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

[Study on the anticancer activities of the Clematis manshrica saponins in vivo].

OBJECTIVE: To study the anticancer activity of the Clematis manshrica saponins in vivo. METHOD: Anticancer activities were tested in mice with experimental tumor (S180, HepA and P388) in vivo. RESULT: The Clematis manshrica saponins showed a significant anticancer activities on Sarcoma-180, HepA and P388 implanted in mice. In S180 sarcoma, the average tumor inhibition rates were 42.78%, 52.06% and 58.25% (P < 0.05-0.01) respectively; The mean inhibition rates were 37.44%, 52.05% and 59.36% (P < 0.05-0.001) in Hep A tumor separately; while in P388 tumor, the mean inhibition rates were 34.50%, 46.78% and 54.39% (P < 0.05-0.01), respectively. CONCLUSION: The results indicate that Clematis manshrica has obvious antitumor effects against various transplanted tumor in mice.

Animals↗

PubMed2006

[Successful monotherapy with S-1 in three cases of recurrent/advanced breast cancer non-responsive to anthracycline and taxane anticancer drugs].

We had 3 patients with recurrent/advanced breast cancer in whom a notable reduction in the size of the targeted tumors was seen following administration of S-1 (TS-1), a new oral pyrimidine fluoride anticancer drug. All of the patients had received taxane and/or anthracycline anticancer drugs as prior therapy; however, they were judged to be non-responsive to the drugs. The size of the targeted tumor decreased to 55.7% after 3 courses of the therapy in Patient 1. The tumor disappeared at completion of the third course in Patient 2, although the therapy was temporarily suspended during the second course due to adverse drug reactions, and the therapy was then resumed after 2-week drug withdrawal. Patient 3 was able to undergo long-term therapy, consisting of 8 courses for 11 months, and the size of the tumor reduced to 58.1%. No serious adverse drug reactions to S-1 occurred in our 3 patients. It is thought that less toxicity enabled Patient 3 to undergo long-term therapy. We consider S-1 to be a useful anticancer drug for treatment of taxane and/or anthracycline resistant recurrent breast cancer.

Aged↗

PubMed2006

How to design a phase I trial of an anticancer botanical.

Phase I trials are an important part of traditional drug development in oncology. Such trials address two key issues: safety and dose. Currently, there is a dearth of phase I trials of anticancer botanicals. This may result from the apparently widespread view that a history of human use precludes the need for early-phase study. However, the safe use of a botanical by the population at large does not guarantee safety when the botanical is used in combination with other agents in the complex medical setting of oncology. Several cases of unpredictable adverse events have been recorded following the use of botanicals by cancer patients. We propose a simple, robust design for phase I trials of anticancer botanicals. This design incorporates important characteristics of botanical medicines including low toxicity, prior data on a likely safe dose, a limit on the highest dose it is feasible to administer, and the unknown relationship between dose-toxicity and dose-response curves. Two principal design features are the use of predetermined dose levels and the direct measurement of a response endpoint such as survival or immunity. This response end point can be used to determine the optimal dose if toxicity is acceptable at all dose levels. Increasing the use of phase I methodology would ensure a more systematic development of botanicals as anticancer agents. This would likely increase the chance that at least one such agent would be proven to extend lives.

Antineoplastic Agents, Phytogenic↗

PubMed2006

Histone deacetylase inhibitor, trichostatin A, increases the chemosensitivity of anticancer drugs in gastric cancer cell lines.

Epigenetic alterations of the histone acetylation play an important role in the regulation of gene expression associated with cell cycles and apoptosis that may affect the chemosensitivity of gastric carcinomas. Recently, a histone deacetylase inhibitor, trichostatin A (TSA), was proven to be a chemo-sensitizer on human erythroleukemia cells. With the aim of improving the chemotherapeutic efficacy of gastric carcinoma, the effect of TSA on the chemosensitivity of several anticancer drugs in gastric carcinoma cells was investigated. Human gastric cancer cell lines, OCUM-8 and MKN-74, and 5 anticancer drugs, 5-fluorouracil (5-FU), paclitaxel (PTX), oxaliplatin (OXA), irinotecan (SN38) and gemcitabine (GEM) were used. In both gastric cancer cell lines, a synergistic anti-proliferative effect by the combination of TSA (30 ng/ml) with 5-FU, PTX or SN38 showed a synergistic anti-proliferative effect in OCUM-8 and MKN-74 cells. TSA increases the expression of p21, p53, DAPK-1 and the DAPK-2 gene in both OCUM-8 and MKN-74 cells. In conclusion, TSA is a promising chemotherapeutical agent in combination with anticancer drugs of 5-FU, PTX and SN38 in gastric cancer cell lines. The up-regulation of p53, p21, DAPK-1 and DAPK-2 might be associated with the synergistic effect of TSA.

Antineoplastic Agents↗

PubMed2006

Diverse resveratrol sensitization to apoptosis induced by anticancer drugs in sensitive and resistant leukemia cells.

Naturally occurring dietary compound resveratrol (RES), possessing chemopreventive and cytostatic properties, has been shown as potent sensitizer for apoptosis induced by a variety of anticancer drugs. Cell cycle analysis in sensitive promyelocytic leukemia HL60 cell line and its multidrug-resistant variant HL60/VCR (P-gp positive) treated with RES resulted in cell cycle arrest in S-phase in both cell variants. Flow cytometry measurements showed diverse activities of RES in combination with anticancer drugs doxorubicin (DOX), cycloheximide (CHX), busulfan (BUS), gemcitabine (GEM) and paclitaxel (PTX), in some cases resulting in apoptosis induction, preferentially at the expense of S-phase. Thus, RES could become a candidate to enhance the efficacy of combination anticancer therapy in a variety of human cancer cells inclusive leukemias.

Anticarcinogenic Agents↗

PubMed2006

[Anticancer therapeutic effect of SEA-linked and membrane-bound HSP70-expressed intestine-carcinoma vaccine].

OBJECTIVE: To develop a novel dual-modified vaccine, the superantigen-linked intestine-carcinoma cells expressing membrane-bound heat shock protein 70 (HSP70), and further examine its anticancer therapeutic effect. METHODS: The pre-established intestine carcinoma CT26 line expressing membrane-bound heat shock protein 70 (HSP70) was amplified and incubated with superantigen fusion protein, staphylococcal enterotoxin A (SEA) fused with transmembrane sequence (SEA-TM), thereby the dual-modified vaccine was prepared after inactivation. The anticancer efficacy of the vaccine was examined. RESULTS: The laser confocal microscopy and flow cytometry showed that there co-existed much HSP70 and SEA on the vaccine membrane surface. Both of the single-modified vaccines, the SEA-linked vaccine and membrane-bound-HSP70-expressing one, displayed marked tumor suppression, a prolonged survival period, augmented lymphocyte proliferation and higher NK and CTL activity in the vaccinated mice when compared with its counterpart. Furthermore, the dually modified vaccine induced lymphocyte proliferation most intensively, generated the highest NK and CTL activity as well as the strongest tumor rejection in the vaccinated mice. The survival period of the mice was further prolonged. CONCLUSION: A new vaccine, SEA-linked and membrane-bound-HSP70-expressing intestine-carcinoma cells can induce more potent anticancer immunity and produce better therapeutic efficacy.

Animals↗

PubMed1991

[Development of slow releasing anticancer drug based with absorbable biomaterial chitin].

To have a comparatively more slowly releasing anticancer drug with effectiveness, Plachitin was prepared by chemical combination of CDDP and chitin (poly-N-acetyl-D-glucosamine). Chitin is absorbed by the living body over several months. To investigate the slow releasing property, it was implanted in thigh muscle of mice and rabbit. Pt level in different organs and in urine was measured at regular intervals. Pt level in implanted muscles was higher in comparison to low serum level in mice. It was released slowly over 1 to 2 months in mice, whereas in rabbit it took about three weeks. Pt releasing period of the Plachitin was different according to the adopted method of implantation. Anticancer effect of Plachitin was investigated by injecting 180 sarcoma cells in mouse peritoneal cavity and subsequent implantation of Plachitin. In control groups chitin was used instead of Plachitin. The survival rate of mice in the Plachitin group after 14 days was higher than in the chitin group, and the anticancer effect of the Plachitin was confirmed.

Absorption↗

PubMed1991

[Combination chemotherapy of HO-221, a derivative of benzoylphenylurea with various anticancer agents against human cancer xenografts in nude mice].

Antitumor effect of HO-221, a derivative of benzoylphenylurea, has been previously studied against seven human cancer xenografts in nude mice established and maintained in our laboratory. In this study, the effect of combination chemotherapy was examined with six of the above seven human cancer cell lines. These consisted of four gastric cancers (H-55, H-111, H-81 and H-154), one breast cancer (H-31) and one pancreatic cancer (H-48). HO-221 was used in combination with one of the following widely used anticancer drugs; mitomycin (MMC), adriamycin (ADM), CDDP, VP-16 and 5-fluorouracil (5-FU). When the tumor growth inhibition rate (IR) by combination of two drugs (at 1/2 MTD for each drug) exceeded both of IR obtained separately with single drug at 1/2 MTD, the combination regimen was rated as showing an additive effect. When IR by combination of two drugs at the same dose level exceeded both of IR obtained separately by MTD of each single drug, the regimen was rated as showing a synergistic effect. Histological changes and side-effects were also taken into consideration for the evaluation of the drug. Combination of HO-221 and MMC produced an additive effect against H-55 and H-111, a synergistic effect against H-81. In the treatment of H-31 which was highly susceptible to these drugs, a remarkable effect was shown in both IR and cellular changes even by combination using 1/2 MTD and 1/4 MTD doses. Combination with ADM at 1/2 MTD for both produced an additive effect against H-111 and H-48. Combination at MTD produced a marked antitumor effect against H-111 and a strikingly remarkable combination effect was confirmed. Combination with CDDP produced an additive effect against H-81 and a synergistic effect against H-154. Moreover, the weight loss by this combination regimen was far less than that by single administration of CDDP at MTD. An additive effect was demonstrated by combination with VP-16. Combination with 5-FU produced minimal combination effect. HO-221 was thus found to have a high antitumor effect by combination with various anticancer agents that are at present widely used clinically. HO-221 is expected to be a promising anticancer drug in its clinical application.

Animals↗

PubMed1990

[Targeting anticancer chemotherapy dispersed in lipid contrast medium in hepatoblastoma in childhood].

Fourteen cases of malignant liver tumor in childhood were experienced in our department during past 14 years. Since 1984 we have performed preoperative targeting anticancer chemotherapy using oily anticancer agents such as THP-adriamycin 30 mg/m2. These oil emulsion was making with 20 mg amounts of THP-adriamycin dissolved in 5 ml urographin and 15 ml volume of lipiodol. These mixture were administered by catheterizing the hepatic artery under X-ray monitoring in 6 cases with hepatoblastoma. Remarkable anticancer effects of this targeting chemotherapy were achieved, the serum AFP level and tumor size both showing a decrease in all cases, and the resectability of tumor showing a increase in 5 among 6 cases in comparison with 50% resectability before 1983.

Adolescent↗

PubMedDate not supplied

Gamma linolenic acid alters the cytotoxic activity of anticancer drugs on cultured human neuroblastoma cells.

Gamma linolenic acid (GLA) by itself shows anti-tumor activity on various neoplastic cells in culture. We investigated the combined effect of GLA and anticancer drugs on two human neuroblastoma cell lines. The cytotoxic effect of Vinca alkaloids such as vincristine (VCR), vindesine (VDS) and vinblastine (VBL) was about 2-fold enhanced when GLA was added simultaneously to the growth medium. On the other hand, that of platinating agents such as cisplatin (CDDP) and carboplatin (CBDCA) was inhibited by GLA supplementation. The cytotoxic activity of other anticancer agents was not affected by GLA. Pharmacokinetic studies on VCR and CDDP demonstrated that intracellular accumulation of [3H]-VCR was about 1.5-fold increased in the cells pretreated by GLA, while, on the contrary, that of CDDP was rather decreased; cellular efflux of either drug was not affected. Malon dialdehyde (MDA) formation induced by supplemented GLA was not influenced by either VCR or CDDP. These results indicate that GLA exerts differential effects on the kinetics of anticancer drugs.

Antineoplastic Agents↗

PubMed1990

[Treatment of carcinomatous effusion with oily anticancer agents dissolved in lipiodol].

The oily anticancer agents dissolved in lipiodol used for arterial administration against various solid tumors in our department were found to be applicable to treat for pleural or peritoneal carcinomatosis experimentally and clinically. The pharmacokinetic study with rat model showed oily anticancer agents were retained in a high concentration in the peritoneal cavity compared to water-soluble anticancer agents. In our pilot clinical study all patients with pleural or peritoneal carcinomatosis showed improvement cytologically and physically.

Adult↗

PubMedDate not supplied

The A.H.E.A.D. method: a quantitative automated measurement of the hematotoxicity of anticancer drugs.

Among the limiting side-effects of anticancer drugs, hematological toxicity is the most frequent. Hematological analysis focuses on nucleated blood cells from mouse peripheral blood or hematopoietic organs (bone marrow, spleen, thymus). We have developed an automated method called A.H.E.A.D. (Automated Hematotoxicological Evaluation of Anticancer Drugs) allowing us routinely to screen chemical products for hematotoxicity, simultaneously with in vivo and in vitro antitumoral assays. Data are collected after a simple dilution of biological samples without any additional isolation, enrichment or purification process. The measurements are performed through an electronic Coulter counter and a slightly modified pulse-height model C1000 analyzer connected on-line to a computer. In addition to nucleated cell counts, this method allows us to get information about cell volume distribution within a given population of leukocytes. In bone marrow, a single assay provides simultaneous information on the relative contents of red, lymphoid, polymorphonuclear and blast cells. We present results obtained with this method during the hematological toxicity studies of some standard anticancer drugs. Besides drug induced alterations, the A.H.E.A.D. method allows monitoring of the recovery of hematological tissues characterization of growing populations of precursors renewing the hematopoietic organs.

Analysis of Variance↗

PubMed1986

[A new anticancer drug sensitivity test using the microplate culture and surviving tumor cell staining method].

We have developed a new anticancer drug sensitivity test using the short-term microplate culture and viable cell staining method, and the details of this method are reported. The tumor cells are cultured with the anticancer drugs for 2 days and 4 days. After culture, the microplate is centrifuged. The surviving tumor cells are fixed with ethanol and stained with crystal violet. After washing out the remaining crystal violet, 200 microliters of sodium lauryl sulfate is put into each microwell and the absorbance of each is measured. When we examined this method using leukemic cell lines, we found that the numbers of cells were in proportion to the absorbance, and that the surviving cells could be counted by the absorbance within the range of 0.4 to 1.7. On the assumption that the effective range is more than 60% of the cytotoxicity index (CI), tables of CI classified into drugs, concentrations and duration of culture for each leukemic cell line were made. With these tables, comparison of the anticancer drugs and subsequent selection of the effective ones became easier. This method is simple, rapid and convenient for handling a large volume of material. Its application to further clinical practice is therefore expected.

Antineoplastic Agents↗

PubMed1986

[Sensitivity of esophageal cancer to anticancer agents and supplementary chemotherapy combined with surgical treatment].

The authors examined the sensitivities of esophageal cancer to Bleomycin (BLM), Peplomycin (PEP), Cisplatin (CDDP) and 5-FU by the INAS method using 3H-thymidine or 14C-formate as labeled precursors, and determined the concentrations of anticancer agents in cancer lesions by the Band Culture method. On the other hand, the authors investigated the superiority or inferiority of various methods of BLM administration by observing the prevention effect of BLM on the development of experimental esophageal cancer in rats. Forty-three cases out of 76, 57%, showed a sensitivity to BLM, 60% to PEP, 38% to CDDP and 56% to 5-FU. As to the types of roentgenological findings, the superficial and tumorous types showed a high sensitivity rate. As to the types of macroscopical findings, the protruded and superficial types showed a high sensitivity rate. As to the types of histological findings, well differentiated squamous cell carcinoma showed a high sensitivity rate. Sensitivity was higher in metastatic lymph nodes than in main cancer lesions. Tumor tissues which had undergone previous hyperthermic management (at 42 degrees C) showed a higher sensitivity than those which had not. PEP at a half dose brought about the same grade of anticancer effect as BLM. The sensitivities of esophageal cancer to various anticancer agents showed individual differences among clinical cases. Therefore, combination chemotherapy for esophageal cancer was thought to be an effective administration method. The divided administration of small doses of BLM was thought to be more superior than the one-shot administration of a large dose for esophageal cancer. The results of the INAS sensitivity test were perfectly coincident with the effects of chemotherapy in clinical cases of esophageal cancer.

Animals↗