Anna Barzi

The immunodepressive and hematotoxic activity of imidazole-4-carboxamide 5-(3,3-dimethyl-1-triazeno) in mice

The immunodepressive and bone marrow stem cell-reducing activities of imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazeno) (DTIC), an antitumoral agent reported to possess little immunodepressive capacity in man, have been investigated in mice and compared with those displayed by cyclophosphamide (Cy). In this species, single doses of DTIC could profoundly depress antilymphoma allograft resistance as well as the number of antibody-producing cells after primary and secondary stimulation with sheep erythrocytes. The highest immunodepressive activity was observed when DTIC was given before antigen and the effect observed was substantially more long lasting than seen with Cy, which was, however significantly more active on a milligram per kilogram basis. In contrast, both agents displayed a quantitatively equal activity in reducing bone marrow stem cells. It is concluded that DTIC can be an effective immunodepressant and that this activity may have clinical implications.

Chelating agents as potential antitumorals. 2-quinolylhydrazones and bis-2-quinolylhydrazones. I

Summary A number of pyruvic acid, methylpyruvate and pyruvic carboxaldehyde 2-quinolylhydrazones have been synthesized. Some bis-2-quinolylhydrazones were also obtained during the reaction with pyruvic carboxaldehyde. All these compounds have been evaluated for cytotoxicity and most display a significant in vitro activity against a variety of cell lines.

Metal(II) complexes of 2,2′-bipyridyl-6-carbothioamide as anti-tumor and anti-fungal agents

Abstract Complexes of Fe(II), Co(II), Ni(II), Cu(II), Cd(II), Pd(II), Pt(II) and Zn(II) with the anti-tumor agent 2,2′-bipyridyl-6-carbothioamide ( bpyta, 1 ) were prepared and characterized. All these metal(II) complexes were screened for their cytostatic activities in vitro against murine P388 leukemia. The copper(II) complex 2f was found to be 12-fold more active than ligand 1. bpyta and its complexes were also evaluated for their anti-fungal activities. Some of the studied complexes displayed significant anti-fungal activity which, however, was lower than that of the parent ligand.

8-Aza Analogues of Deaza Purine Nucleosides. Synthesis and Biological Evaluation of 8-Aza-1-deazaadenosine and 2′-Deoxy-8-aza-1-deazaadenosine

Abstract The syntheses of 7-amino-3-(β-D-ribofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (8-aza-1-deazaadenosine) (2) and 7-amino-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (2′-deoxy-8-aza-1-deazaadenosine) (3) by glycosylation of the anion of 7-chloro-3H-1,2,3-triazolo[4,5-b]pyridine are described. The anomeric configuration as well as the position of glycosylation were determined by 1H, 13 NMR, UV and N.O.E. difference spectroscopy. The cytotoxicity of these nucleosides against several murine and human tumor cell lines is discussed. Compounds 2 and 3 proved to be good inhibitors of adenosine deaminase.

Implications and problems in analysing cytotoxic activity of hydroxyurea in combination with a potential inhibitor of ribonucleotide reductase

The cytotoxicity of hydroxyurea in combination with 2,2′-bipyridyl-6-carbothioamide (a potential inhibitor of ribonucleotide reductase) on P388 murine leukemia is reported. Synergistic activity was studied using various interpretations of the isobologram method and the combination index method. We evaluated the pros and cons of these methods and their overall usefulness. In our opinion, to obtain all possible information from a compound association, it is important to choose a formally correct method that (a) can quantitatively evaluate synergism or antagonism, (b) may offer the possibility of averaging final results, (c) needs a minimal amount of experimental data, and (d) is rapid. Moreover, we emphasize both the utility of testing at least three molar ratios of compound association and the importance of carefully choosing the fractional inhibition used in calculating the combination effect. Such evaluation of drug combinations gives information essential to the preparation of new anticancer drug regimens and to the early assessment of biochemical interactions.

In Vitro Chemosensitivity of Newly Diagnosed and Relapsing Acute Non-Lymphoid Leukemia Patients

We evaluated the in vitro sensitivity of circulating blasts from 25 newly diagnosed and 7 relapsing ANLL patients to drugs employed in vivo for inducing remission. Ten of the 14 newly diagnosed complete responders were in vitro sensitive to cytosine arabinoside and daunorubicin, whereas 10/11 non-responders were resistant to both agents. Although cells from all 7 relapsing patients were in vitro sensitive to the remission inducing agents, only 4 entered complete remission. Even if only indicative, these findings suggest that the poor prognosis of relapsing patients may be due, at least in part, to factors other than drug resistance. Moreover, the chemo-sensitivity test adopted is a better predictor in newly diagnosed than relapsing patients, as indicated by the concordance between in vitro and in vivo results.

Combination chemotherapy with 5-fluorouracil and methyl-CCNU for the treatment of advanced gastrointestinal cancer.

Sixteen patients with advanced gastrointestinal cancer (colorectal 12/16, gastric 4/16) were treated with a combination of 5-fluorouracil (5-FU) plus 1-(2-chlorethyl)-3(4-methyl–cycloexyl)-1-nitrosourea (Me-CCNU). The therapeutic program consisted of orally administered Me-CCNU (140 mg/m2) and intravenous 5-FU (9.5 mg/kg by bolus injection for 5 days). The cycles were repeated at 6-week intervals. At the beginning of the therapy, 11/16 patients were in performance status (PS) 0-1 and 5 patients in PS 2-3. Eight patients developed early progressive disease between the 1st and 2nd course of therapy. Only a minor tumor response was observed in the remaining 50 % of the patients. However, the patients with stabilized disease lived longer (11.8 months) than non-responders (3.5 months).

Immunologic reactivity in patients bearing solid tumors.

The immune reactivity of 50 patients with solid tumors before therapeutic treatment and 26 healthy controls was assessed by both in vitro and in vivo tests. No significant differences between controls and patients were found in peripheral lymphocyte counts or in delayed hypersensitivity to recall antigens. However, impairment of lymphocyte stimulation with phytohemagglutinin (PHA) and a decrease in the number of E-rosette forming cells (E-RFC) were detected in cancer-bearing patients irrespective of tumor type. The results of the present study further confirm the usefulness of the PHA and E-RFC tests in monitoring the immune competence of cancer patients.