A human tumor-cloning system was used to compare the antitumor activity of CI-921, a new amsacrine analog with that of its parent compound (amsacrine gluconate). A total of 48 specimens of 9 histologically different types of human malignancy were evaluable for a direct comparison of the cytotoxic activity. Both compounds were tested simultaneously at 10 micrograms/ml final concentration under continuous exposure. The overall activity was similar for both drugs, but the degree of cross-resistance was low. We concluded that in patients, CI-921 might have a different spectrum of antitumor activity from that of its parent compound.

Amsacrine↗

PubMed1989

Age related randomized comparison of sequentially applied high-dose versus intermediate dose cytosine arabinoside in combination with mitoxantrone (S-HAM) in the treatment of relapsed and refractory acute myeloid leukemia: study design and preliminary results.

In a prospective randomized trial, the pending question was addressed whether Cytosine arabinoside (Ara-C) should be applied at high or intermediate dose to patients with relapsed or refractory acute myeloid leukemia. Based upon the previously established regimen of the sequential application of Ara-C and Mitoxantrone (S-HAM) patients below 60 years of age were randomized to receive Ara-C at either 3.0 g/m2 vs 1.0 g/m2 per dose while older patients were randomly assigned to either 1.0 g/m2 or 0.5 g/m2 Ara-C. At the present early stage 51 patients have entered the study and 37 are currently evaluable for response and toxicity. Complete remissions were achieved in 14 of 28 patients below 60 years of age and in 3 of 8 older cases. Predominant side effects consisted of nausea and vomiting, diarrhea and stomatitis. Further recruitment of patients and longer follow-up is required for the assessment of the various treatment arms.

Age Factors↗

PubMed1988

Cytotoxic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5-monophosphate (fludarabine, NSC 312887) in a human tumor cloning system.

A human tumor cloning system was utilized to screen for in vitro antitumor effects of the new purine antimetabolite 9-beta-D-arabinofuranosyl-2-fluoroadenine 5-monophosphate. Two hundred and thirty-one specimens were evaluable for drug sensitivity information (i.e. greater than or equal to 20 colonies on control plates). The overall in vitro response rates (defined as a less than or equal to 50% survival of tumor colony forming units) at two different concentrations of the new drug (0.1; 1.0 micrograms/ml) were between 21 and 24%. The new drug had significant antitumor activity (i.e. in more than 35% of specimens of those with at least five tested specimens) only against non-Hodgkin's lymphoma and breast cancer.

Antimetabolites, Antineoplastic↗

PubMed1987

Detection of murine S180 cells expressing a multidrug resistance phenotype using different in vitro test systems and a monoclonal antibody.

Doxorubicin (adriamycin) preconditioned S180 cells were more resistant to doxorubicin. The resistance was detected by three different methods (short-term test, colony assay, tissue culture assay). The doxorubicin-resistant S180 cells express the pleitrop drug resistance phenotype. There exists a multidrug resistance to doxorubicin, dactinomycin (actinomycin D), vincristine and colchicine. In addition, collateral sensitivity was found to fluorouracil (5-fluorouracil) and methotrexate. This multidrug phenotype is in accordance with the pleiotropic phenotype of colchicine-resistant CHO cells. Resistant S180 cells express a glycoprotein of Mr 170 kd determined by indirect immunofluorescence using a monoclonal antibody (Mab 265/F4) to the P-glycoprotein of colchicine-resistant CHO-cells. The P-glycoprotein could be an important prognostic factors for tumors with multidrug resistance.

Animals↗

PubMed1986

Improved plating efficiencies for human tumors cloned in capillary tubes versus Petri dishes.

As now constituted, the human tumor cloning assay performed in Petri dishes has several limitations including: (a) not all patients' tumors form colonies in the assay; (b) the plating efficiencies (number of colonies formed/number of cells plated) are low; and (c) a large number of tumor cells are required to perform drug sensitivity testing. In this study the use of capillary tubes, as vessels in which to clone human tumors, is compared to the use of 35-mm Petri dishes. In 100-microliters capillary tubes the optimal plating efficiencies are found with 50,000 cells/vessel (500,000 cells/ml), while in 35-mm Petri dishes the optimal plating efficiencies are found with 500,000 cells/vessel (250,000 cells/ml). In head to head comparisons of plating efficiencies of 183 human tumors (18 different histological types), the median plating efficiency was 5-fold higher (range, 1.16-37.00) for the capillary tubes than for the Petri dishes. This improved plating efficiency was noted for nearly all of the histological tumor types examined. The improved plating efficiencies noted with the capillary system indicate that the Petri dish method may be too selective and not reflect the total number of clonogenic units in a human tumor. In addition, the higher plating efficiencies noted with the capillary system may be exploited to solve some of the problems noted with the conventional Petri dish method.

Cell Count↗

PubMed1985

Immunological detection of Chinese hamster ovary cells expressing a multidrug resistance phenotype.

A monoclonal antibody (IgG1) has been prepared that specifically detects Chinese hamster ovary cells expressing a multidrug-resistant phenotype. This antibody recognizes the membrane P-glycoprotein (Mr 170,000) associated with drug resistance as determined by enzyme-linked immunosorbent assay with purified P-glycoprotein and by Western blot analysis of cell extracts from drug-resistant and drug-sensitive cells. By immunofluorescence methods, the antibody also reacts strongly with viable and ether:ethanol-fixed resistant cells but does not react with the parent drug-sensitive cell line. Thus, this antibody can bind with live cells allowing discrimination by immunohistochemistry between drug-resistant and drug-sensitive Chinese hamster ovary cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1985

In vitro comparison of vinzolidine and vinblastine: a model for methods of evaluation of analogues in a human tumor cloning system.

Four statistical techniques are described for comparing the in vitro cytotoxic activity of an analogue and its parent compound in the human tumor cloning system. These techniques include: the Spearman rank correlation coefficient; a sequential pairwise analysis; the kappa statistic for measuring agreement; and the McNemar test of symmetry. These statistical procedures were applied to results from 54 human tumor specimens that were simultaneously tested against multiple concentrations of the Vinca alkaloid vinblastine and its semisynthetic analogue, vinzolidine. Based on the percentage of survival of tumor colony-forming units in the human tumor cloning system, vinzolidine was shown to have a 26% in vitro response rate with a spectrum of activity across major tumor types. However, all four statistical procedures indicated that the activity of vinzolidine was not superior to that of its parent compound. Of the four statistical procedures examined, the sequential pairwise design appears to be best suited for comparing in vitro activity of an analogue and its parent compound and could result in a savings of both time and resources required for such comparisons.

Cell Survival↗

PubMed1984

Cytotoxic activity of echinomycin in a human tumor cloning system.

A human tumor cloning system was utilized to screen for in vitro antitumor effects of the investigational anticancer agent Echinomycin. Tumors from 562 patients (24 different histological tumor types) were placed in culture. Two hundred fifty-five specimens were evaluable for drug sensitivity information (i.e., greater than or equal to 20 colonies in control plates). The overall in vitro response rates (defined as less than 50% survival of tumor colony-forming units) at three different doses of Echinomycin (0.001, 0.01, and 0.1 micrograms/ml) were between 16% and 19%. Echinomycin showed minor in vitro cytotoxic activity in breast and colon cancer, and in sarcoma. A comparison of these in vitro results with the results of phase-II clinical trials, as they become available, will help to evaluate the utility of the human tumor cloning system for predicting clinical antitumor activity of new antineoplastics.

Cell Survival↗

PubMed1984

Use of a human tumor cloning system to evaluate analogs of methotrexate and mitoxantrone.

We have utilized a human tumor cloning system to compare the antitumor activity of trimetrexate ( TMQ ), a new dihydrofolate reductase inhibitor, and ametantrone , a new anthracenedione, with that of analogs already in clinical trial (methotrexate and mitoxantrone). Sixty-nine of 136 tumors plated for the TMQ study and 84 of 228 tumors plated for the ametantrone study were evaluable for drug-sensitivity assays. The overall in vitro response rates (defined as a less than or equal to 50% survival of tumor colony-forming units) for TMQ were 20% and 23% at 0.1 and 1 microgram/ml, respectively; for ametantrone they were 13%, 21%, and 26% at 0.1, 1, and 10 micrograms/ml, respectively. The overall in vitro activity for both new compounds was similar to that of their clinically used analogs, but TMQ was active in eight of 47 methotrexate-resistant specimens and ametantrone in nine of 62 mitoxantrone-resistant specimens. A comparison of these in vitro results with the results of phase II clinical trials with both drugs should allow an evaluation of the utility of the human tumor cloning system for predicting clinical antitumor activity of analogs of currently available antineoplastic agents.

Anthraquinones↗

PubMed1980

[Animal experiments for intratumoral chemotherapy with bleomycin (author's transl)].

The intense clinical interest in bleomycin as an anti-tumour agent has led to different methods of administration in an attempt to administer sufficiently high concentrations of the drug to the tumor. Therefore, a study was designed to determine the distribution and the therapeutic effect of a bleomycin emulsion and aqueous bleomycin after different routes of application. The tissue distribution of radioactively labelled bleomycin emulsion and aqueous bleomycin was determined in tumor-free CF 1 and tumor-bearing (EL 4, L 1210) C 57 Bl 6 and DBA 2 mice after local (s.c., i.t.) and systemic (i.v.) injection. The distribution studies for aqueous 57Co-bleomycin showed increased activity in the injection sites and the lymph nodes draining the injection sites after s.c. and i.t. injection compared to i.v. administration of the drug. In comparison to the aqueous local administration, the application of 57Co-bleomycin emulsion resulted in a disproportional increase of the 57Co-bleomycin concentration at the injection sites and in the draining lymph nodes. To prove the therapeutic relevance of the bleomycin tissue distribution tumor-bearing (line 10) strain 2 guinea pigs were treated with different modes of bleomycin. Animals with already lymphogenously metastasized tumors have been cured by means of low i.t. doses of the bleomycin emulsion. Guinea pigs treated with i.t. administration of aqueous bleomycin need, compared to the bleomycin emulsion, five times higher doses for tumor-free survival. Intravenously treated animals died either because of progressive tumor growth or because of toxic bleomycin effects. These findings made by animal experiments favor the i.t. treatment of head and neck carcinomas with a bleomycin emulsion.

Animals↗

PubMed1974

Lead the way.

Explore the source record for details and available documents.

Aged↗

PubMedDate not supplied

Binding of monoclonal anti-interleukin 2 antibody to nucleoli in acute leukemia blast cells.

Neutralizing anti-IL-2, anti-IL-3, and anti-IL-6 monoclonal antibodies (MAbs) were used for the immunoenzymatic detection of the respective cytokines in blast cells of 38 patients with acute myeloid (AML) and lymphoid (ALL) leukemias by the APAAP-technique. In 20/24 AML-cases (83%) blast cells showed intranuclear staining with MAb anti-IL-2 (DMS-1). In 17 cases reaction was restricted to the nucleoli, in 4 cases additional cytoplasmic staining was observed. Only 2/13 (15%) of the ALL cases showed anti-IL-2 staining. In contrast to IL-2, neither IL-3, IL-6 nor IL-2R alpha-chains were detected in any of the acute leukemias tested. The anti-IL-2 staining of nucleoli in AML cells is distinct from the cytoplasmic staining which is observed in PHA-activated normal lymphocytes and in a minority of AML cells.

Antibodies, Monoclonal↗

PubMedDate not supplied

In vitro drug sensitivity testing with agar-containing glass capillaries.

Capillary cloning has been shown to have advantages over conventional cloning of human tumor cells in Petri dishes. We have recently published in this Journal an optimization of the capillary method towards homogeneous colony distribution and high cloning efficiency. In the present study this modified capillary cloning system was investigated for its feasibility for drug sensitivity testing. For the human breast cancer cell line MDA-231 and the drug sensitive Chinese Hamster Ovary cell line CHO-AB as well as for its multidrug resistant mutant CHO-C5 a similar linear dose response effect was obtained with the capillary cloning system and with the Petri dish system. The capillary cloning system, however, was 2 to 4 fold more sensitive for the detection of cytotoxic drug effects. It was concluded that the optimized capillary cloning system is well suited for drug sensitivity testing.

Agar↗

PubMedDate not supplied

Homogeneous growth of tumor cell colonies in agar containing glass capillaries.

The capillary cloning system has been shown to have advantages over conventional cloning of human tumor cells in Petri dishes. In the present study a further optimization towards homogeneous colony distribution and high cloning efficiency is described. For reasons of reproducibility the study focused on cell lines, i.e. three human linew (MDA-231, HT-29, L363) and one rodent line (CHO-AB). Major variables investigated were the gel length, the capillary tube diameter, the tube sealing and buffer system, and the cell number. Criteria for optimal tumor colony growth included homogeneous colony distribution along the gel, mean colony size and cloning efficiency. It was found that colony distribution as well as overall colony growth depended largely on the gel length, i.e. on the volume of tumor cell containing agar applied per capillary tube. The results showed that optimal tumor cell colony growth was achieved in 100 ul capillary tubes of 1.2 mm internal diameter filled with 30ul, yielding a gel length of 27 mm. Colony formation did not significantly differ between sealed and unsealed tubes, provided that HEPES buffer was added. It was concluded that, for practical reasons, sealing of tube ends and therefore utilization of HEPES buffer is not necessary. In a head to head comparison, cloning efficiency was equal or higher in capillary tubes than in Petri dishes. The capillary cloning system is an alternative for drug development as well as for predictive drug testing. Its major advantage is the utilization of fewer tumor cells.

Agar↗