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Biomedical subjects

B Lathan

Publications and source records attributed to B Lathan.

At least 37 records · Page 2Linked to original sources

The Second International Symposium on Hodgkin's Disease. Workshop III: Recommendations for future clinical trials.

In the opinion of the participants of the workshop, the following problems should be addressed with high priority: 1st, a clear definition of the 10%-15% of patients who should receive radiotherapy only; 2nd, reduction of toxicity of combined modality approaches for patients in localized stages with risk factors; and 3rd, definition of a poor-prognosis subgroup of patients in stages IIIB/IV for whom more efficient treatment programs must be developed. Dose intensification in the form of ABMT as the prominent example of high dose intensity should be tested in these patients. If this approach proves its efficacy, the concept of dose intensification could be extended to other patients with advanced disease. Results of recent trials in Hodgkin's disease suggest that the cure rates which increased considerably between 1960 and 1980 have reached a plateau. Further improvements that can be realistically expected will be small and studies to prove such progress need large numbers of patients ('megatrials') to avoid 'false negative' results. Such megatrials could be performed as large international or even intercontinental trials. To some extent, overviews could substitute for megatrials, if sufficient high-quality randomized studies addressing a specific question are available for a meta-analysis. The installation of an international steering committee was recommended, which should stimulate and coordinate world-wide efforts for the solution of the remaining problems in the treatment of Hodgkin's disease.

Antineoplastic Combined Chemotherapy Protocols↗

Combined effect of very early intensification and prolonged post-remission chemotherapy in patients with AML.

The study combines the effects of prolonged postremission chemotherapy with that of very early intensification. 900 adult patients at all ages with newly diagnosed AML uniformly received TAD for induction and consolidation followed by monthly myelosuppressive maintenance for 3 years. In patients of 60+ years with persistent bone marrow blasts a second TAD course was given. In all patients of less than 60 years a second induction course started on day 21 even in aplasia with no blasts. Second induction was randomly either TAD or HAM. In the younger age group 69% attained CR and similar in the two arms the CR rate after 5 years is 35%. Including the 50% patients attaining CR in the higher age group the CR rate after 5 years is 32%. In 40 patients receiving allogeneic BMT and 21 patients receiving autologous BMT in first CR relapse free survival is similar to that from chemotherapy alone in a matched pair analysis. We conclude that age adapted very early intensification followed by prolonged postremission chemotherapy represents a therapeutic progress.

Adolescent↗

Evaluation of an amsacrine analog in a human tumor cloning system.

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↗

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↗

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↗

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↗

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↗

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↗

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↗

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↗