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PubMed1985

Histidinol-mediated enhancement of the specificity of two anticancer drugs in mice bearing leukemic bone marrow disease.

The possibility was investigated that L-histidinol-anticancer drug combinations may provide increased tumor cell eradication and eliminate in vivo bone marrow toxicity of proliferation-dependent anticancer agents in animals bearing an established, intrafemoral bone marrow disease. It was previously demonstrated that L-histidinol, a structural analogue of the essential amino acid L-histidine, improves the specificity of cytarabine (ara-C) and 5-fluorouracil (FUra) in DBA/2J mice bearing intraperitoneal L 1210 leukemia. Accordingly, DBA/2J mice were given iv injections of 1 X 10(6) L1210 leukemia cells 3 days before histidinol-anticancer drug treatments. During the postinjection, pretreatment interval, injected tumor cells populated the femoral marrows, shown by clonogenic assays and flow cytometric analyses. Following various drug treatments, quantitative and selective survival assays were performed of normal femoral cells and of clonogenic L1210 leukemia cells isolated from the femurs of treated mice. These experiments demonstrated that L-histidinol not only protected the marrow cell population from both ara-C and FUra, but also increased significantly the toxicities of these agents for the intrafemoral tumor cells. Thus L-histidinol mediates a substantial increase in the specificities of ara-C and FUra in mice bearing an established bone marrow leukemic condition.

Animals↗

PubMed1985

[In vitro sensitivity test of a cultured human ovarian cancer cell line to anticancer agents].

In vitro tests were performed to assess the sensitivity to six anticancer agents-ACT-D, ADM, CDDP, CQ, 5-FU and MMC-of a JOHYL-1 (ascites type) cell line from human dysgerminoma which was used as challenge strain. For comparative assessment, anticancer sensitivity was expressed as the ratio of IC50 and IC90 to LD50 (i.v.) in mice. Drug dose-response and time-response curves were plotted, and the IC50 ratio was calculated, for each test compound in order to investigate the mechanism of anticancer action. The results obtained were as follows. CQ proved to be remarkably active and ADM fairly active against JOHYL-1 (ascites), but 5-FU, CDDP and MMC varied remarkably with the parameter of measurement employed. Analysis of IC50 ratio data and patterns of cell growth inhibition indicated the growth-inhibitory effect of CDDP to be concentration-and time-dependent. The results of the present study are in close accord with the pattern of action reported in the literature.

Animals↗

PubMed1985

[Clinical application of a sustained release anticancer pellet].

During a 6.5-year period from March 1978, 136 patients with brain tumors, which were diagnosed as gliomas or metastatic brain tumors during surgical operation, were treated by the application of sustained release anticancer pellets in seven institutes. Histological diagnosis disclosed that the majority of the tumors were malignant gliomas (61 cases), metastatic brain tumors (35 cases), and benign astrocytoma (17 cases). The anticancer agents (250 mg of 5FU, 1.5 mg of MMC, 250 mg of BUdR and 6,000 iu of urokinase) were sealed in a Silastic silicone tube of 6 mm in diameter, 0.25 mm in wall thickness, and 12 mm in length. The daily delivery of the drugs was (2-3)/10,000 of the original volume. This treatment was combined with surgical and irradiation therapy with or without general chemotherapy. The median survival time of patients with malignant gliomas was 545 days (18 months). The 1-year survival rate was 65.63%, and the 3-year survival rate 16.2%. On the other hand, in patients with benign astrocytomas, the median survival time was 1,500 days (4.1 years), 1-year survival rate 83.75%, and 3-year survival rate 42.84%. In those with metastatic brain tumors, the median survival time was 280 days, 1-year survival rate 43.87%, and 3-year survival rate 24.84%. The present findings revealed that the tube-type anticancer pellets cannot inhibit the growth of the brain tumors located 5 cm from the pellets.

Antineoplastic Agents↗

PubMed1979

Chemical characterization and biological activity of an anticancer agent of marine origin.

Clinical interest in the pharmacology of medicinals from marine organisms has heightened due to anticancer effects indicated for Mercenaria marine clam components. This report further characterizes the anticancer principle. Hydrophilic products were extracted by aqueous and/or salting-out methods followed by dialysis. Organic solvent extraction produced a new family of active agents related to the hydrophilic component. Thin layer and liquid column chromatography as well as enzymatic degradation were used to secure a more pure product for analysis. Assay included P388 leukemia and B16 melanoma. Oligonucleotide fractions and smaller components were observed to increase survival rate; treated mice remained at 67% survival when control animals had reached zero. A many-fold purified product was effectively reduced from 300 mg/kg body weight to 5 mg/kg to achieve anticancer activity. Chemical analysis suggested a product composed of carbohydrate, phosphate, peptide, and an unidentified material. Acid hydrolysis revealed the presence of hexoses, pentoses, and a full spectrum of amino acids. Several distinct components found to comprise the active samples may act as the effective product or as a carrier.

Animals↗

PubMed1981

[Effect of anticancer drugs on in vitro survival of cell lines derived from various gynecologic tumors (author's transl)].

Effect of various anticancer drugs on in vitro survival of gynecologic tumor cells were investigated by using established cell lines derived from human ovarian adenocarcinoma (HOC-21), endometrial adenocarcinoma (HEC-1B), and cervical squamous cell carcinoma (SKG-1). As compared with other established cell lines, 1) HOC-21 cells were more sensitive to Cis-platinum, Adriamycin, and actinomycin-D. 2) HEC-1B cells were more sensitive to progesterone. 3) SKG-1 cells were more sensitive to bleomycin and mitomycin-C. These results are consistent with the clinical effects of various anticancer drugs, and established cell lines derived from various human gynecologic tumors are useful to select effective anticancer drugs in vitro.

Adenocarcinoma↗

PubMed1984

[Analysis of the mechanism of cancer metastasis by using anticancer agents].

For the analysis of the mechanism of cancer metastasis, effects of anticancer agents on the NK activity of spleen cells and on the artificial metastasis of B-16 melanoma cells were comparatively studied. The inhibitory effect of these anticancer agents on the growth of B-16 melanoma inoculated to foot pad of C57/BL6 mice was also examined. The growth of B-16 melanoma was inhibited by intravenous administration of 6 mg/kg of MMC, 18 mg/kg of KW-2083 and 5 mg/kg of CDDP, but not of 6 mg/kg of KW-2083. The NK activities in spleen cells of C57/BL6 mice administered with 6 mg/kg of MMC and 18 mg/kg of KW-2083 were decreased, but they were not decreased in mice administered with 6 mg/kg of KW 2083 and 5 mg/kg of CDDP. Significant increases in the number of artificial pulmonary and liver metastasis were observed in mice administered with 6 mg/kg of MMC and 18 mg/kg of KW-2083. It is suggested that the depression of NK activity induced by anticancer agents results in the promotion of metastatic disease.

Animals↗

PubMed1983

[In vitro method determining sensitivity of anticancer agents by incorporation of radioactive precursors].

A new sensitivity test of anticancer agents was developed to measure the lethal effects of cancer cells by the incorporation of radioactive precursors. The thousand cancer cells were cultured in a microplate in the presence of anticancer agents. These cells were exposed to radioactive precursors. Two or three days later, the cancer cells were harvested on a glass fiber filter by a multiple automatic cell-harvester and the incorporation of precursors was counted by a liquid scintillation counter. In this study, the in vivo results of drug testing in animal model systems were compared with drug sensitivities. Mice inoculated Ehrlich ascites cells were treated with various kinds of anticancer drugs. The development of the cells was compatible with the result of the sensitivity test. The growths of Lauson and ME-180 cells derived from human cancers implanted subcutaneously to nude mice were also well correlated with this sensitivity test.

Animals↗

PubMed1984

[Anticancer drug sensitivity tested by tumor stem cell assay].

Accurate in vitro anticancer drug sensitivity is helpful for successful chemotherapy of cancer patients. The purpose of the present study was to evaluate the tumor stem cell assay for the selection of effective drugs for individual patients with cancer and for the in vitro phase II screening of new anticancer drugs. Sixty-six specimens obtained from cancer patients were tested drug sensitivity by this assay. The results showed that this assay as an excellent technique for testing in vitro sensitivity of anticancer drugs against tumor cells from specimens removed from individual patients. The in vitro results correlated with in vivo response data in 93% of the instances observed in vitro-in vivo associations and a true negative rate was 100%.

Antineoplastic Agents↗

PubMed1984

Potentiation of anticancer agents by new synthetic isoprenoids. I. Inhibition of the growth of cultured mammalian cells.

In this study, 9 new synthetic isoprenoids with 9-10 isoprene chains were tested. One-fifth of the D10 value (concentration of drug that reduced colony-formation ability to 10% that of control) for each isoprenoid was calculated from dose-response curves of Chinese hamster V79 cells or human HeLa cells in culture. That dose was combined with various anticancer agent [1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-n itrosurea HCl, bleomycin A2 (BLM), cisplatin, doxorubicin (Dx), 5-fluorouracil, mitomycin, and 6-mercaptopurine] to test whether isoprenoids can potentiate the cytotoxic effect of anticancer agents against cultured mammalian cells. Among the 9 isoprenoids tested, decaprenoic acid, dacaprenylamine.HCl, and N-(p-methylbenzyl)decaprenylamine.HCl significantly potentiated BLM and Dx. Some isoprenoids increased intracellular levels of anticancer agents. Both enhanced uptake and reduced efflux of Dx were observed.

Animals↗

PubMed1984

A four-day subrenal capsule assay for testing the effectiveness of anticancer drugs against human tumors.

The subrenal capsule assay may predict to which anticancer drug a given patient's tumor is sensitive and may also be used to screen new anticancer drugs. The present study documents that the use of this model requires a histological assessment of both the exploitability of a subrenal capsule assay and the extent of drug-induced antitumor lesions. Thirty-five tumors from 34 patients with solid tumor were submitted to a subrenal capsule assay in a total of 1130 male B6D2F1 mice. After being biopsied, each tumor was dissected by a pathologist and cut into 50 pieces (1.5 X 1.5 X 1.5 cu mm), and one piece was implanted under the renal capsule of 35 mice; the mean tumor diameter was measured on Day 0. Mice were randomized into groups of 6 to 10 animals each. On Days 1, 2, and 3, mice were treated either with placebo (control group) or with various anticancer agents. On Days 4 or 6, mice were sacrificed, the mean tumor diameter measured, and the tumor-bearing kidney fixed in Bouin's picroformol solution and processed for histological analysis after staining with hematein -eosin. Seven histological parameters were blindly rated in a semiquantitative fashion yielding a compound score ( PAPAN ) which estimated the overall quality of each xenograft between -3 and +11. On Day 4, as opposed to Day 6, mean lymphocytic infiltration was 3-fold lower (p less than 0.01), and the rate of xenografts containing well-preserved cancer cells was 2-fold larger (p less than 0.01) in three different tumor specimens. Twenty-two of 31 (71%) assays were evaluable, as defined by a histological quality control test. In those, drug effects were demonstrable by statistically significant differences among groups in 2 assays (9%) by using the relative variation in tumor size as an index of drug effectiveness and in 12 assays (54%) by PAPAN histological score. This suggests the higher sensitivity of histological scoring over tumor size measurements. Moreover, no correlation between relative variation in tumor size and PAPAN was demonstrable with statistical significance indicating the poor reliability of tumor size measurements as an index of the antitumor effectiveness of cytostatic drugs.

Adenocarcinoma↗

PubMed1993

[Studies of combined treatment of radiofrequency hyperthermia with anticancer agents or irradiation for invasive bladder cancer].

Using an in vitro colony forming assay system, the cytotoxic effects of anticancer agents alone, adriamycin (ADM) and bleomycin (BLM), and the combined effects of hyperthermia and anticancer agents on cultivated KK-47 cells were investigated. When the hyperthermia was combined with various concentrations of ADM ranging from 0.005 to 0.1 microgram/ml and BLM from 0.01 to 1.0 microgram/ml, enhanced cell killing effects were obtained at the concentration of less than 0.02 microgram/ml of ADM and with an increase of BLM concentration. In DNA specimens obtained from the livers of chick embryos inoculated with human tumor cultivated cells, the polymerase chain reaction technique was used to amplify a DNA fragment specific to the beta-globin gene. By detecting these amplified DNA fragments, the feasibility of efficiently detecting metastatic cells present in chick embryo was demonstrated in vivo. Hyperthermic therapy showed inhibitory effects on the growth of metastasized cultivated cells in a thermal dose-dependent manner. Combination therapy of ADM, mitomycin and carboplatin and hyperthermia had an enhanced inhibitory activity on the growth of metastasized cultivated human tumor cells derived from bladder cancer. Hyperthermia using radiofrequency-capacitive heating in combination with irradiation or anticancer agents, was performed in a total of 56 patients with T2 to T4 invasive urinary bladder cancer. A tumor regression rate of 50 percent or more was obtained in 21 of these 56 patients. We have to follow up the patients for longer periods more precisely to evaluate the role of these treatments.

Adult↗

PubMed1995

[Cell cycle regulation by anticancer agent].

Some anticancer agents induce cell cycle arrest. We analyzed the effect of anticancer agents on cell-cycle regulators, such as CDK. Our data suggested that arresting cells in the G2-phase of the cell cycle by cisplatin might be regulated by dephosphorylation of cdc2 kinase. Butyrolactone I inhibits both cdc2 and CDK2 kinase in the cell-free system. The cytotoxic effect of paclitaxel shows mainly in the M-phase of the cell cycle. Suramin inhibits cdc2 kinase. UCN-01, a protein kinase-C inhibitor, also inhibits both cdc2 and CDK2 kinase. Some anticancer agents induce apoptosis.

Antineoplastic Agents↗

PubMed1995

Anticancer activity of beta-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration.

Naturally occurring nucleosides and all anticancer nucleoside analogue drugs are in the beta-D configuration. L-(-)-dioxolane-cytidine [(-)-OddC] is the first L-nucleoside analogue ever shown to have anticancer activity. This compound was converted within cells to its mono-, di-, and triphosphate metabolites and was incorporated into DNA. As with cytosine arabinoside, conversion to the monophosphate was catalyzed by cellular deoxycytidine kinase, which was essential for cytotoxicity. However, unlike cytosine arabinoside, (-)-OddC was not susceptible to degradation by deoxycytidine deaminase. Because (-)-OddC inhibited the growth of hepatocellular and prostate tumors that are generally difficult to treat, it is a promising candidate for additional testing. Our results indicate that there is a great deal of variability in the chiral specificities of cellular enzymes and demonstrate how these differences can be exploited in the design of better anti-viral and anticancer drugs.

Animals↗

PubMedDate not supplied

Nonresponsiveness of the metastatic human lung carcinoma MV522 xenograft to conventional anticancer agents.

The human lung carcinoma cell line MV522 was previously noted to produce extensive metastasis to the lungs, spleen and lymph nodes after subcutaneous transplantation into athymic nude mice. Animals eventually succumb to these metastases, and not primary tumor growth. The ability to produce extensive metastasis after a simple subcutaneous injection in 100% of animals (> 100 tested to date) would be an advantage when screening compounds for anticancer activity. To validate the utility of this xenograft model for testing anticancer agents, we tested the ability of 10 anticancer drugs to either inhibit primary tumor growth and/or prolong life span of MV522-bearing animals. Among the 10 antitumor conventional agents, only mitomycin C and taxol demonstrated primary tumor growth inhibition. Mitomycin C produced a mild increase in median life span of 41% to 63%, while taxol had inconsistent effects. The metastatic MV522 carcinoma model appears to reflect clinical resistance of primary non-small cell lung cancer to conventional chemotherapeutic agents and should be useful for testing new anti-cancer drugs.

Animals↗

PubMed1994

Binding of non-homologous series of anticancer drugs to glutathione.

The interaction of 17 anticancer drugs with reduced glutathione was studied by charge-transfer reversed-phase thin-layer chromatography and the hydrophobicity, the specific hydrophobic surface area and the relative strength of interaction was calculated. Only 7 anticancer drugs showed significant interaction with glutathione, the relative strength of interaction depended significantly neither on the hydrophobicity nor on the specific hydrophobic surface area of the drugs. As the interacting drugs are basic compounds it is reasonable to suppose that their interaction with the acidic glutathione is based on Coulombic forces. The direct binding of these drugs to glutathione makes it probable that glutathione may influence the biological activity of the bound anticancer drugs.

Antineoplastic Agents↗

PubMed1995

[Effects of anticancer drugs and combination effects of anthracyclines on the hypoxic cells of head and neck cancer].

Head and neck cancer has hypoxic compartment. The hypoxic cells are resistant to anticancer drugs and thought to be one of the causes of recurrence. We examined effects of anticancer drugs on the hypoxic cells using HEp-2 human laryngeal cell line. Anticancer drugs, CDDP, peplomycin (PEP), 5-FU, THP-adriamycin (THP-ADR), and adriamycin (ADR), were incubated with cells in hypoxic condition (5% CO2 and 95% N2) for 72 hours. Drug effects were measured by proliferation rates (IC50). IC50 of PEP increased 22.89 folds in hypoxic cells. IC50 of CDDP and 5-FU also increased 1.86 and 2.27 folds respectively. However, IC50 of THP-ADR and ADR remained same in the hypoxic cells. It was proved that THP-ADR and ADR were effective for the hypoxic cells. The combination effect with THP-ADR and CDDP or PEP were more than additive against the hypoxic cells. It was suggested that the combination with THP-ADR and CDDP or PEP are effective for head and neck cancer which contains hypoxic cell compartment.

Antibiotics, Antineoplastic↗

PubMed1995

[Development of anticancer-agent-releasing microcapsules for chemotherapy combined with embolo-hyperthermic therapy].

For the purpose of combining chemotherapy with embolo-hyperthermic therapy, we have developed microcapsules made of ferro-magnetic amorphous metal flakes that are additionally capable of releasing anticancer agents. The capsules can be used in a suspension to infuse them into a tumor with transcatheter arterial embolization (TAE). The capsules generate heat in an alternating magnetic field (185 kHz), which avoids heat generation by the body itself. At a certain intensity of the magnetic field, the maximum temperature of the capsule is determined by the Curie point of the amorphous metal. After reaching the maximum temperature, the capsule maintains the temperature by itself within an accuracy of +/- 0.5 degree C. In animal experiments, the capsules generated sufficient heat for interstitial hyperthermia. The tissue concentration of the anticancer agent after TAE with the capsules is maintained at 10 to 20 times higher than that after intraarterial infusion of the anticancer agent solution. These results suggest the usefulness of this method for embolo-hyperthermic therapy combined with intensive chemotherapy without invasive temperature measurement.

Animals↗

PubMed1976

Distribution of anticancer activity in higher plants.

The systematic distribution in higher plants of general anticancer activity, high-interest anticancer activity, and high-interest compounds is presented. Special emphasis is placed on those taxonomic groups offering, by virtue of their high-interest activity and/or compounds, the greatest potential as sources of useful anticancer agents.

Animals↗