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Biomedical subjects

M D'Incalci

Publications and source records attributed to M D'Incalci.

At least 235 records · Page 13Linked to original sources
PubMed1988

Response of chemically induced primary colon tumours of the mouse to flavone acetic acid (NSC 347 512).

Flavone acetic acid (FAA) is a compound with proven activity against various transplantable colon cancers in mice. In this study it was evaluated against primary colon tumours, chemically induced by methylazoxymethanol in outbred CF1 mice. FAA was given i.v. at doses of 70 or 100 or 150 mg kg-1 every 7 days for 6 weeks. Only 4 out of 60 FAA treated mice died of toxicity. FAA reduced tumour number and tumour burden compared to control mice (P less than 0.05 at least), with no apparent dose-response relationship. Antitumour activity of FAA was comparable to that of 5-fluorouracil (5-FU) used as standard. Moreover, FAA was more effective that 5-FU against large tumours. FAA levels in plasma and different tissues (including colonic neoplastic lesions) after a single i.v. dose of 150 mg kg-1 were investigated. Tumour FAA levels appear insufficient to be responsible for the antitumour activity based only on a direct FAA cytotoxic effect. The results confirm clinical interest in FAA and suggest that mechanisms other than direct cytotoxicity may be involved in its activity.

Animals↗
PubMed1988

Response to flavone acetic acid (NSC 347512) of primary and metastatic human colorectal carcinoma xenografts.

The antitumour activity of flavone acetic acid (FAA) was evaluated against two human colorectal carcinoma (HCC) lines, HCC-P2988 and HCC-M1410, transplanted into nude mice. On repeated i.v. injection of 200 mg kg-1 every 4 days FAA was moderately active against the s.c. growing HCC-P2988. HCC-M1410 transplanted s.c. was almost unresponsive in the same experimental conditions. In contrast, FAA (200 mg kg-1 i.v. every 4 days, repeated three times) significantly reduced liver tumour colonies produced by the HCC-M1410 cells injected intrasplenically into nude mice. These findings suggest that FAA has potential activity against human colorectal carcinoma, particularly against liver metastases.

Animals↗
PubMed1987

In vitro and in vivo methazolastone-induced DNA damage and repair in L-1210 leukemia sensitive and resistant to chloroethylnitrosoureas.

DNA damage caused by methazolastone [an analogue of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide which does not require metabolic activation] was investigated in L-1210 leukemia which is sensitive to this drug and in a L-1210 subline [L-1210/N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU)] which is resistant to both chloroethylnitrosoureas and methyltriazenes. Both in vitro and in vivo metazolastone caused formation of DNA alkali-labile sites (assessed by alkaline elution techniques) which were present in similar amounts and repaired at a similar rate in L-1210 and L-1210/BCNU. This suggests that these lesions are not crucial to methyltriazenes activity. DNA alkali-labile sites may be due to the removal of 7-methylguanine by 7-methylguanine-DNA glycosylase which showed the same activity in L-1210 and L-1210/BCNU. Flow cytometry studies revealed that in L-1210 but not in L-1210/BCNU methazolastone induced an arrest of cells in SL-G2-M phases. This blockade was delayed, occurring after at least two cell divisions after drug treatment and therefore appeared temporally unrelated to the presence of DNA alkali-labile sites. There was three times more O6-methylguanine-DNA methyltransferase in L-1210/BCNU than in L-1210 suggesting that methylation of O6-guanine is an important lesion for methyltriazenes activity and resistance to this drug may be linked to its repair.

Animals↗
PubMed1987

DNA cross-linking responses of human malignant glioma cell strains to chloroethylnitrosoureas, cisplatin, and diaziquone.

Cell strains derived by culture of malignant glioma (astrocytoma grade III-IV) surgical specimens were tested for the production of DNA interstrand cross-links (ISC) and DNA-protein cross-links following treatment in vitro with 1-(2-chloroethyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine), 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea (PCNU), cis-dichlorodiammineplatinum(II) (cisplatin), and 3,6-diaziridinyl-2,5-bis(carboethoxyamino)-1,4-benzoquinone (diaziquone). ISC and DNA-protein crosslinks were measured by means of the DNA alkaline elution technique. Large differences among the cell strains were observed in DNA cross-linking responses to individual agents. The DNA responses to the chloroethylnitrosoureas, cisplatin, and diaziquone were largely independent of each other, except for a weak correlation between ISC responses to chloroethylnitrosoureas were distributed bimodally, in accord with a phenotypic distinction between Mer+ and Mer- cells. ISC responses to cisplatin and diaziquone showed significant variation among cell strains, but the distributions were not bimodal. The results demonstrate the existence of diverse DNA cross-linking response patterns among cell strains from different tumors of a given histological type.

Aziridines↗
PubMed1987

Human tumor cell lines with pleiotropic drug resistance are efficiently killed by interleukin-2 activated killer cells and by activated monocytes.

Two human cell lines, the colon carcinoma Lovo and the transformed intestinal I-407, and their variants (Lovo/Dx and I-407/Dx), with pleiotropic resistance to cancer chemotherapeutic drugs, were examined for their susceptibility to human Interleukin-2-activated killer cells and to activated monocytes. These non-specific or broadly specific effector cells expressed cytotoxicity levels on pleiotropically resistant tumor cells comparable to those of the parental cell populations. This finding provides a rationale for immunological approaches designed to eradicate residual tumor cells surviving and resistant to cytotoxic chemotherapy.

Antineoplastic Agents↗
PubMed1987

Pharmacokinetics of 7-con-O-methylnogarol in patients with solid tumors.

The pharmacokinetics of 7-con-O-methylnogarol were investigated by HPLC assay with fluorometric detection in nine cancer patients with normal hepatic and renal function, after a 2-h infusion of 160 or 200 mg/m2. The drug disappeared from plasma biexponentially with a mean elimination half-life of 38 +/- 3 h; the mean apparent volume of distribution and the plasma clearance were 805 +/- 91 1/m2 and 14 +/- 2 1/h per m2. Within 48 h of administration, urinary excretion of the drug and its metabolite 7-con-O-methyl-N-demethylnogarol accounted for 2%-15% and 0.1%-6% of the dose, respectively. Neither 7-con-O-methylnogarol nor its N-demethyl derivative was conjugated with glucuronic acid or sulfate in detectable amounts.

Aged↗
PubMed1987

Pharmacokinetics of VM 26 given intrapericardially or intravenously in patients with malignant pericardial effusion.

Three patients with lung cancer (1 SCLC, 2 NSCLC) and pericardial malignant effusion received 100 mg/m2 Teniposide (VM 26) i.v. and, 1 week later, 50 mg/m2 intrapericardially. Plasma, pericardial, and urine levels of the drug were measured in all patients after the two treatments by a HPLC assay. After intrapericardial administration, a high VM 26 concentration was found in the pericardial cavity and slow systemic drug absorption was observed. Since the drug AUC after intrapericardial administration was approximately 15-21 times that after i.v. administration, it could be that this treatment is more effective against neoplastic deposits localized in the pericardium. Even though this small series does not permit conclusions to be drawn on the efficacy of VM 26 given intrapericardially, the lack of local toxicity, minimal systemic toxicity, and the response observed in two out of three patients given intrapericardial VM 26 suggest that further investigation should be carried out on this method of VM 26 administration.

Aged↗
PubMed1987

Antiproliferative properties of flavone acetic acid (NSC 347512) (LM 975), a new anticancer agent.

The antiproliferative activity of flavone acetic acid (LM 975) was investigated on human adenocarcinoma cell lines (HCC-P2998, HCC-M1544, HCC-M1410, HT 29, LoVo), on a murine colon adenocarcinoma cell line (Colon 26), on murine pancreatic adenocarcinoma cells growing in primary culture (Pan 03) and on human normal fibroblasts (N1). No cytotoxic effects were found against human normal fibroblasts. LM 975 was active against murine adenocarcinoma Pan 03 and Colon 26, known to be sensitive in vivo too and, to variable extents, on human adenocarcinoma cell lines. LM 975 in vitro cytotoxic potency was relatively low. The high concentrations (1.0-1.4 mM) required to obtain a cytotoxic effect are, however, pharmacologically reasonable since they are comparable with drug plasma levels in mice or in patients treated with tolerable doses. After a relatively short LM 975 treatment (2 h) DNA, RNA and protein synthesis were inhibited in different proportions. In more sensitive cells LM 975 appeared to inhibit RNA synthesis more than DNA and protein synthesis. Inhibition of macromolecule synthesis after 2 h exposure was completely reversed in 24 h recovery. After 2 h treatment no detectable DNA breakage was found by the alkaline elution method, thus corroborating the idea that this compound does not act by causing DNA damage.

Adenocarcinoma↗
PubMed1987

Histone H1(0) is synthesized by human lymphocytic leukemia cells but not by normal lymphocytes.

Using a two-dimensional gel electrophoresis system (sodium dodecyl sulphate/acetic acid-urea-hexadecyltrimethylammonium bromide) coupled with fluorography, we investigated the synthesis of H1 isoproteins in leukemic cells obtained from peripheral blood of eight children suffering from acute lymphoblastic leukemia (ALL) (four T-ALL, three common ALL, and one B-ALL) and in normal peripheral lymphocytes. H1 was synthesized in leukemic cells but not in normal lymphocytes. Inhibition of DNA synthesis with hydroxyurea and 1-beta-D-arabinofuranosylcytosine induced an increase of relative synthesis of H1(0) in leukemic cells but did not induce any detectable synthesis of H1 in normal lymphocytes. H1(0) synthesis was also undetectable in peripheral lymphocytes of leukemic children in complete remission after chemotherapy and in lymphocytes of a homozygotic twin of a leukemic patient. H1(0) may be a marker of malignant transformation of lymphocytes and as such could be of use for early detection of relapse in patients with acute lymphocytic leukemia in apparent complete remission.

Electrophoresis↗
PubMed1987

Doxorubicin distribution in human breast cancer.

Using a high-performance liquid chromatographic method coupled with fluorimetric detection, we evaluated plasma pharmacokinetics of doxorubicin (DX) and tissue distribution in seven patients suffering from locally advanced breast cancer. Tumor biopsies were performed 30 minutes and 24 hours after DX injection. In addition at 48 hours, during surgery, biopsies were obtained from primary breast cancer, nodes, and other accessible tissues, and DX concentrations were analyzed. A triexponential equation gave the best fit for plasma levels and the values (mean +/- SE) were: elimination half-life, 37.6 +/- 4.9 hours; volume of distribution, 605 +/- 61 L/m2; and clearance 200 +/- 27 ml/min/m2. There was greater interindividual variability in tumor DX concentrations than in plasma concentrations. DX reached much higher (range at 48 hrs, 1.54-14.17 micrograms/g) and longer-lasting concentrations in tumor than in plasma. At 48 hours tumor concentrations were 55.2-337.4 times the plasma concentrations. DX concentrations in normal breast were lower or similar to those in breast carcinoma. DX levels were very low in fat and skin, slightly higher in muscle, and very high in normal or metastasized lymph nodes.

Breast Neoplasms↗
PubMed1986

Comparison of metabolism and activity of an aryldimethyltriazene and an aryldiethyltriazene.

The antitumoral activity and metabolism of 1-(4-acetylphenyl)-3,3-dimethyltriazene [pAc-(CH3)2] and 1-(4-acetylphenyl)-3,3-diethyltriazene [pAc-(C2H5)2] were studied in mice. pAc-(CH3)2 showed significant antitumoral activity against M5076 ovarian reticular cell sarcoma, L1210 leukemia, EL 4 lymphoma in mice, but not against Lewis lung carcinoma. pAc-(C2H5)2 was inactive in all these murine tumors and was much more toxic than pAc-(CH3)2. pAc-(CH3)2 and pAc-(C2H5)2 were rapidly metabolized in vitro and in vivo to their respective monoalkyltriazenes and to 4-aminoacetophenone (pAc-NH2). In vitro, 79% of the dimethyltriazene was metabolized to its monomethyl analogue, but only 27% of the diethyltriazene was metabolized to the monoethyltriazene. The monoalkytriazenes were almost completely biotransformed to pAc-NH2 by a 9000 g liver fraction. The metabolic pattern in the in vitro study was comparable to that found in vivo.

Animals↗
PubMed1986

H1 variant synthesis in proliferating and quiescent human cells.

The synthesis of histone H1 isoprotein species in human cells of several different types and in several different physiological states was studied. Up to five H1 and two H1 degrees isoprotein species could be resolved by two-dimensional electrophoresis. All five H1 isoprotein species were synthesized in exponentially growing cultures of IMR-90 human fibroblasts; in quiescent IMR-90 cells the synthesis of three H1 isoprotein species was greatly decreased while the synthesis of two others was much less affected. When DNA synthesis in exponentially growing cultures of IMR-90 was inhibited, the pattern of H1 isoprotein synthesis became similar to that found in quiescent cultures. Other human cells, isolated from blood, yielded similar results. These results suggest that the pattern of H1 synthesis is the same for cells in non-S phases of the cell cycle and in quiescent cells. Thus for histone H1 in human cells the relationship of the variant synthesis pattern to the growth state and DNA replication is similar to that of the core histone H3 but not that of H2A.

Adult↗
PubMed1986

In vivo studies with the novel anticancer agent mitozolomide (NSC 353451) on Lewis lung carcinoma.

Mitozolomide is one of the most effective drugs against Lewis lung carcinoma in the mouse. Two IP doses of 40 mg/kg (days 6 and 15 after IM transplantation of 3LL) or four doses of 20 mg/kg given at various intervals (starting from day 6) increased survival time by 100%. A single IP dose of 80 mg/kg was toxic, and 10 mg/kg was ineffective even when this dose was given on eight occasions. The pharmacokinetics of mitozolomide was investigated in 3LL-bearing mice by HPLC assay. Peak drug levels were achieved in tumor 15 min after IP treatment, after which they declined according to first-order kinetics, with a half-life of 80-100 min (the same as in plasma). No dose-dependent kinetics was observed. Flow cytometry studies showed an accumulation of 3LL cells in G2M 24 h after drug treatment. This cell cycle perturbation was reversed 96 h after the inactive dose of 10 mg/kg, but not after the effective dose of 40 mg/kg.

Animals↗
PubMed1986

Comparison between VP 16 and VM 26 in Lewis lung carcinoma of the mouse.

The antitumoral activity and pharmacokinetics of VP 16 and VM 26 were comparatively investigated in Lewis lung carcinoma (3LL)-bearing mice. When the two drugs were given at equitoxic doses, in single or repeated treatment, the superior antitumoral activity of VM 26 was clear. Compared to VP 16, VM 26 had a different pattern of distribution, with a larger volume of distribution, a longer elimination half-life time and a lower clearance. The tissue to plasma AUC ratios indicated that VM 26 concentrated more in tumor and heart while VP 16 gave highest concentrations in liver and intestine. Flow cytometry studies showed that VM 26 was more potent than VP 16 in causing cell cycle perturbation of 3LL cells growing in primary culture. VM 26 displayed cytotoxic activity at a concentration in the medium one-tenth that of VP 16. The uptake of VM 26 by 3LL cells was 15 times that of VP 16.

Animals↗
PubMed1986

Mitozolomide activity on human cancer cells in vitro.

The growth inhibitory effects, the reduction of [3H]-TdR incorporation and the perturbation of the cell cycle induced by the new agent mitozolomide on the M14 human melanoma cell line and on the SW626 human ovarian cancer cell line were compared to those produced by BCNU. Flow cytometry showed an interesting difference: at the high concentration mitozolomide induced an accumulation of cells in S middle and S late-G2-M phase of the cell cycle whereas BCNU caused only a block in S late-G2-M. Further studies were aimed at investigating the susceptibility of freshly isolated human ovarian cancer cells to pharmacologically reasonable mitozolomide concentrations. Only in one out of 16 primary cultures of human ovarian cancers was mitozolomide able to induce cell cycle perturbation, suggesting that ovarian carcinoma cells may not be sensitive to this drug.

Aged↗