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Biomedical subjects

M D'Incalci

Publications and source records attributed to M D'Incalci.

At least 199 records · Page 11Linked to original sources
PubMed1990

Cytotoxicity and DNA damage caused by 4-demethoxydaunorubicin and its metabolite 4-demethoxy-13-hydroxydaunorubicin in human acute myeloid leukemia cells.

4-Demethoxydaunorubicin (4-DMDR) and its major metabolite 4-demethoxy-13-hydroxydaunorubicin (4-DMDRol) were investigated for their cytotoxicity and mode of action against human leukemic cells. The drug and its metabolite appeared to be equally potent as both inhibitors of cell proliferation and inducers of DNA double-strand breaks in the OCI AML-3 cell line and cells derived directly from patients with acute myeloid leukemia (AML). This suggests that 4-DMDRol plays an important role in the antileukemic activity of 4-DMDR.

Adult↗
PubMed1990

Flavone acetic acid distribution in human malignant tumors.

The pharmacokinetics of flavone acetic acid (FAA) after a dose of 4.8 mg/m2 given i.v. over 1 h was investigated in 13 patients with different solid tumors. The mean volume of distribution and clearance were 52 +/- 4 l/m2 and 2.6 +/- 0.2 l/h x m2, respectively. A tumor or metastasis biopsy was obtained from six patients 2 h after the end of infusion. Tumor FAA levels ranged from 39.6 to 148.8 micrograms/g and were similar to those obtained after a therapeutic i.v. dose of 200 mg/kg FAA in animals bearing Pan/03 tumor, which is very sensitive to the drug. Although FAA tumor concentration could be detected only during one interval and we therefore cannot draw a definitive conclusion, differences in the agent's antitumor activity in mice and patients (i.e. very active in the former and inactive in the latter) are apparently not due to discrepancies in drug distribution and pharmacokinetics.

Adult↗
PubMed1990

DNA damage and sequence specificity of DNA binding of the new anti-cancer agent 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo-[2.2.1] heptane dimaleate (Dabis maleate)

The DNA damage and the sequence specificity of guanine-N7 alkylation produced by the novel, positively charged, antineoplastic agent 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo-[2.2.1] heptane dimaleate (Dabis maleate) and its uncharged tertiary amine analogue 1,4-bis(2'-chloroethyl)-1,4-diazacyclohexane (Dabis analogue) were investigated in L1210 cells and isolated DNA. Both compounds are cytotoxic in vitro causing an arrest of L1210 cells in G2/M phase of the cell cycle. In isolated DNA, Dabis maleate alkylates guanine at the N7-position with some differences in specificity compared to other alkylating agents (e.g. nitrogen mustard). Significant differences are also evident between Dabis maleate and Dabis analogue, suggesting that Dabis analogue is not the sole alkylating species of Dabis maleate. Using the alkaline elution technique a moderate number of DNA interstrand cross-links were detected in L1210 cells treated with both compounds, which were completely repaired within 24 h. Dabis maleate and Dabis analogue do not cause DNA single strand breaks or DNA protein cross-links at the doses at which DNA interstrand cross-links were detected.

Animals↗
PubMed1990

Synergism between 5-fluorouracil and N-methylformamide in HT29 human colon cancer line.

In HT29 cells 5-fluorouracil (5FU) cytotoxicity is enhanced by subsequent incubation of cells in medium containing 1% N-methylformamide (NMF). This enhancement does not appear to be related to differences in the repair of 5FU-induced DNA damage. It is proposed that the inhibition of DNA synthesis by NMF (that is reversible and does not result in any detectable toxicity) becomes a lethal event in a cell in which DNA synthesis has already been altered by 5FU exposure. The synergism is sequence dependent (i.e. it does not occur when NMF is given before 5FU) and specific for some cell types as shown by the fact that no synergism was found in L1210 mouse leukaemia cells. In nude mice transplanted s.c. with HT29 cells daily 5FU treatment (for 5 days) followed by daily NMF treatment (for 10 days) caused much greater inhibition of tumour growth than either drug alone or the same combination given in the opposite order (NMF then 5FU). These results, if confirmed on other human colon tumours, could be of clinical interest as a means of increasing the therapeutic efficacy of 5FU in patients with colon cancer.

Adenocarcinoma↗
PubMed1990

Interferon inducers increase O6-alkylguanine-DNA alkyltransferase in the rat liver.

We investigated whether treatment with the interferon inducer polyinosinic-polycytidylic acid and other cytokines (interleukin-1, tumor necrosis factor) or the cytokine inducer lipopolysaccharide modified O6-alkylguanine-DNA alkyltransferase (AT) in rat liver. AT levels were determined in liver extracts using N-[3H]methyl-N-nitrosourea alkylated calf thymus DNA as substrate and an HPLC procedure to measure O6-methylguanine. Doses as low as 0.1 mg/kg i.p. of polyinosinic-polycytidylic acid caused a highly significant increase (P less than 0.01) in AT levels in the liver, evident either 24 or 48 h after treatment. Lipopolysaccharide at the dose of 80 micrograms/kg i.p. also induced AT whereas interleukin-1 (60 micrograms/kg) or tumor necrosis factor (60 micrograms/kg) were inactive. Treatment with human recombinant interferon alpha A/D caused a highly significant increase in AT levels, thus confirming the hypothesis that interferon was probably responsible for the observed effect. These results suggest a link between the immune response and DNA repair mechanisms.

Animals↗
PubMed1990

Pharmacokinetics of intrapleural versus intravenous etoposide (VP 16) and teniposide (VM 26) in patients with malignant pleural effusion.

The pharmacokinetics of etoposide (VP 16) and teniposide (VM 26) were studied after intrapleural administration to 3 patients with lung cancer and malignant pleural effusion. Comparison with the kinetic behavior of intravenously infused VP 16 and VM 26 in the same patients suggests that intrapleural drug delivery achieves higher and longer-lasting pleural concentrations, thus providing a theoretical basis for the palliative treatment of malignant pleural effusions. Although no systemic toxicity was observed after intrapleural administration of either drug, 1 of the 3 patients developed a transient asymptomatic hemorrhagic pleurisy during the first 2 days after the drug, alerting to the possible local toxicity of such treatment.

Aged↗
PubMed1989

Comparison of intracellular drug retention, DNA damage and cytotoxicity of derivatives of doxorubicin and daunorubicin in a human colon adenocarcinoma cell line (LoVo).

Formation of DNA single strand breaks (SSB) was assayed by alkaline elution in LoVo cells treated with doxorubicin, daunorubicin and six derivatives of these drugs modified either in the chromophore or the sugar. Seven compounds showed a biphasic relationship (initial increase and then a decrease) for the formation of DNA-SSB over the concentration range 0.05-10 micrograms/ml. At a drug concentration in the range causing an increase of DNA damage very fast repair of DNA-SSB was observed for 4'-deoxydoxorubicin and 4-demethoxydaunorubicin; the kinetics of DNA-SSB investigated after drug removal at a drug concentration reducing DNA-SSB showed a time dependent increase of DNA damage for both drugs although with different patterns. 4'-Deoxydoxorubicin reduced the effect of radiations on the rate of elution of DNA in a way resembling the formation of DNA interstrand cross links (ISC) at concentrations at which DNA-SSB were reduced. DNA-ISC were not produced by chemical reactions occurring during sample processing for alkaline elution and this derivative was not metabolized by LoVo cells. The IC50 of the anthracyclines were on a several log range, though for most of the derivatives the cytotoxicity curve showed a plateau at growth inhibition of about 15-30% at increasing intracellular drug levels. A relationship between DNA damage and cytotoxicity was observed only in a very small range of DNA-SSB. It is likely that the different effects of these anthracyclines on the formation of DNA-SSB depend on a qualitatively different interaction between drug-DNA and topoisomerase II when the drug concentration is raised.

Adenocarcinoma↗
PubMed1989

Intraperitoneal and subcutaneous xenografts of human ovarian carcinoma in nude mice and their potential in experimental therapy.

Human ovarian carcinomas (HOC) were established s.c. and i.p. in nude mice and the biological characteristics were investigated for 4 xenografts. HOC8 and HOC18, derived respectively from a primary tumor of the ovary and a pleural effusion (from 2 different patients) were established s.c. in nude mice. HOC10 and HOC22, derived from the ascites of 2 patients, were directly established as ascites after i.p. injection in nude mice. The s.c. and i.p. growth behavior of the 4 HOC lines was investigated. HOC18, HOC8 and HOC22 cells produced progressively growing tumor after s.c. injection but HOC10 ascites would not grow s.c. The cell suspension derived from HOC18 only produced carcinomatosis upon i.p. injection, while HOC8 cells produced both ascites and carcinomatosis. The 2 ascites HOC10 and HOC22 produced ascites in nude mice, but only HOC22 formed i.p. carcinomatosis. Histopathological characteristics of the patients' primary tumors persisted in nude mice, regardless of the site of tumor implantation. DNA histograms of the xenografts closely matched the patients' tumors and remained stable at different passages. Cisplatin, adriamycin and cyclophosphamide given i.v. were tested against HOC8 and HOC18 growing s.c. and HOC22 and HOC10 growing i.p. HOC8 showed a significant response to DDP and almost no sensitivity to ADR and CTX. HOC18 showed only moderate growth delay with all 3 drugs. Mice bearing HOC10 and HOC22 ascites had a prolonged survival time after DDP and ADR treatment.

Animals↗
PubMed1989

Temozolomide induced differentiation of K562 leukemia cells is not mediated by gene hypomethylation.

Temozolomide (8-carbamoyl-3-methylimidazo[5,1d]-1,2,3,5-tetrazin-4-(3H)-one), an experimental antitumor agent which spontaneously decomposes to 5-(3,3-methyl-1-triazeno) imidazole-4-carboxamide, the active metabolite of the antineoplastic drug DTIC, causes erythroid differentiation of K562 leukemia cells. The increase in epsilon and gamma globin gene expression after temozolomide treatment does not appear to be due to drug-induced hypomethylation of the genes. In other genes containing many methylated sequences such as the proto-oncogenes c-myc and C-Ha-ras, temozolomide caused no detectable change in methylation. In contrast, in the same genes 5-aza-2'-deoxycytidine induced hypomethylation. Temozolomide caused DNA alkali-labile sites and an arrest of the cell cycle in G2 phase. Ethazolastone (its 3-ethylimidazo analogue) which does not cause differentiation of K562 produced no significant DNA damage and G2 phase blockade. DNA damage rather than hypomethylation may be responsible for induction of differentiation.

Blotting, Northern↗
PubMed1989

High-performance liquid chromatographic determination of 5-bromodeoxyuridine in human plasma.

A new method is described for the determination of submicromolar concentrations of 5-bromodeoxyuridine in human plasma. Sample pretreatment involves cold methanol deproteinization, freezing-thawing and lyophilization. The sample is then analysed by reversed-phase high-performance liquid chromatography. This method is very reproducible and has a detection limit of 0.1 microgram/ml (0.32.10(-6) M). Comparison with other procedures indicates that the method is advantageous as regards sensitivity and specificity and can be readily applied in clinical pharmacological investigations.

Bromodeoxyuridine↗
PubMed1989

Characterization of a novel mouse reticular cell sarcoma M5076 subline resistant to cisplatin.

A novel murine tumor resistant to cis-diamminedichloroplatinum (cisplatin, DDP) was obtained (M5/DDP) after 22 passages in which mice bearing the ovarian reticular cell sarcoma M5076 (M5) were treated with DDP. Although DDP conserved some inhibitory activity on growth of M5/DDP, it was much less effective than on M5. Treatment with DDP did not prolong the survival time of mice with M5/DDP, whereas it markedly prolonged survival of M5-bearing mice. M5 and M5/DDP tumors shared many biological and biochemical features. They were similar histologically, they metastasized reproducibly to the liver and were poorly immunogenic. Their growth rates were comparable; their DNA index, percentage of cells in S phase and intra-cellular glutathione content were also similar. In both tumors, DDP caused an accumulation of cells in S late-G2-M within 24 hr after drug treatment. However, this was efficiently reversed in M5/DDP, whereas it worsened and persisted longer in M5. Cross-resistance was observed between DDP and its analogues carboplatin and iproplatin, but tetraplatin retained marginal activity on M5/DDP tumor. Several alkylating agents tested [L-phenyalanine mustard (L-PAM); cyclophosphamide (CTX); chlorambucil (CLB); 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and dacarbazine (DTIC)] were not totally cross-resistant to DDP, but showed greater activity on M5 than on M5/DDP. Other non-alkylating anti-neoplastic drugs showed a similar degree of activity on M5 and M5/DDP. 5-Aza-2'-deoxycytidine (Aza-d-Cyd) was very effective on both tumors, etoposide (VP-16) and cytosine arabinoside (Ara-C) had no activity and Adriamycin (ADR) was weakly effective.

Animals↗
PubMed1989

Lymphokine-activated killer (LAK) and monocyte-mediated cytotoxicity on tumor cell lines resistant to antitumor agents.

In this study we have examined the susceptibility of tumor cell lines exhibiting different patterns of resistance to chemotherapeutic agents, to the cytotoxic action of lymphokine-activated killer (LAK) cells and activated monocytes. The susceptibility of tumor cells with pleiotropic drug resistance to these cytotoxic mechanisms was not different from that of their parental, chemo-sensitive cell lines. Tumor lines used in this study included three human cell lines (LOVO N and LOVO/Dx, I-407 and I-407/Dx, MCF7 and MCF7a) selected for being resistant to doxorubicin and showing a pleiotropic pattern of resistance, and the murine ovarian reticulum cell sarcoma M5076 and its variants resistant to individual antitumor agents (cisplatin, cyclophosphamide and 5-aza-2'-deoxycytidine). These results demonstrate that drug-resistant tumor cell lines, irrespective of the pattern of resistance, were susceptible to the in vitro cytotoxicity mediated by LAK cells and activated monocytes with levels of lysis similar to those of parental chemosensitive lines. Moreover, freshly isolated tumor cells from ovarian cancer patients unresponsive to different chemotherapeutic treatments (operationally drug-resistant) were significantly killed in vitro by LAK cells. These findings support the concept that activated effector cells have the potential to complement conventional chemotherapy by eliminating drug-resistant tumor variants.

Animals↗
PubMed1989

Distamycins inhibit the binding of OTF-1 and NFE-1 transfactors to their conserved DNA elements.

We investigated the effects of the antiviral agent distamycin A and of a distamycin derivative (FCE 24517) which possesses antineoplastic activity on the binding of some regulatory proteins to DNA. Both compounds inhibited the binding to DNA of the ubiquitous octamer binding factor OTF 1 and of the erythroid specific GATAAG protein (NFE 1). This was shown using the electrophoretic mobility shift assay on a DNA fragment of human gamma-globin gene promoter (-156 to -201), on the same fragment with a point mutation (T to C mutation) known to have an increased affinity of binding for NFE 1, on a DNA fragment of human histone H2B promoter and on a DNA fragment of mouse alpha 1 globin promoter. The ability of distamycin or of FCE 24517 to inhibit the binding was specific for AT-rich sequences since neither drug inhibited the binding of nuclear protein factors to the sequence CCACACCC of the human beta globin gene. Binding to DNA was investigated by evaluating the drugs' ability to protect selected sequences from DNase I digestion (DNase footprinting). Distamycins binding was highly preferential for DNA sequences containing stretches of AT. These studies indicate that chemicals which have a high degree of DNA sequence-specific binding can selectively inhibit the binding of regulatory proteins to DNA. These effects might be responsible for modification of the transcription of specific genes and might to some extent account for these drugs' antiviral and antineoplastic activities. This approach offers potential for the investigation of new such drugs.

Base Sequence↗
PubMed1989

A gas chromatographic mass spectrometric assay for the determination of aphidicolin in plasma of cancer patients.

A gas chromatographic-mass spectrometric (GC-MS) method is described for the determination of the novel anticancer agent aphidicolin in plasma. The extraction was carried out in a solvent mixture of hexane:isopropanol (10:1) and the external standard aphidicolane was added after evaporation of the organic phase. The residue was then redissolved in a derivatizing mixture containing bis(trimethylsilyl)trifluoracetamide as sililating agent, pyridine, and trimethylchlorosilane, and allowed to react at 80 degrees C for 2 h. After GC separation of the derivatized samples, selected ion recording analysis was done, monitoring the ions at mass 523.3 and 448.3 for aphidicolin and aphidicolane, respectively. The mean recovery +/- SD of aphidicolin from plasma was 73.5 +/- 11.6% in the range from 5 to 800 ng. This method was applied to determine aphidicolin plasma levels in three cancer patients in Phase I clinical trials of aphidicolin-17-glycinate administered as a 1-h iv infusion. Two patients received dose of 290 mg/m2 and the third received 435 mg/m2. Aphidicolin plasma levels at the end of infusion were very low, and the drug rapidly disappeared from plasma with a terminal (beta) half-life of 2 h.

Adult↗
PubMed1989

Metabolism and pharmacokinetics of p-(3,3-dimethyl-1-triazeno) benzoic acid in M5076 sarcoma-bearing mice.

The pharmacokinetics of the anticancer agent p-(3,3-dimethyl-1-triazeno) benzoic acid (pCOOH-DMT), a drug now in phase I clinical trial in Europe, was investigated in C57Bl female mice with M5076 reticulum-cell sarcoma that were treated i.v. with 200 mg/kg pCOOH-DMT. The drug disappeared from plasma with a terminal half-life of about 2.5 h. Plasma clearance was approximately 6 ml/min per kg. Distribution studies showed some differences in drug levels in different tissues. The highest levels were found in the tumor, liver, kidney and lung; lower levels were found in the spleen and gut, and the lowest, in the brain. The N-desmethyl derivative of pCOOH-DMT was not detectable in plasma or tissues of mice treated with the drug. Therefore, the previous evidence of low N-demethylation of pCOOH-DMT was confirmed. pCOOH-DMT glucuronide was identified by mass spectrometry and quantified by high-performance liquid chromatography (HPLC) in plasma, tissues and urine samples. pCOOH-DMT glucuronide appears to be the major urinary metabolite of pCOOH-DMT in mice. Another metabolite identified by mass spectrometry and quantified by HPLC in some tissues and urine was pCOOH-DMT glycinate.

Animals↗
PubMed1989

Changes in the synthesis of histone H1(0) and H1 in rat FRTL-5 thyroid cells exposed to thyrotropin.

In absence of thyrotropin (TSH), FRTL-5 rat thyroid cells stop proliferating and lose the functional characteristics of thyroid tissue. FRTL-5 cells regain their differentiated state and their proliferation activity upon addition of TSH. In this study we investigated the synthesis of histone H1 variants and H19(0) in FRTL-5 cells exposed to 10(-8) M TSH, two days after TSH withdrawal. TSH induced the synthesis of some H1 variants and H1. This effect was already evident six hours after TSH addition, thus well before proliferation, DNA or thyroglobulin synthesis was induced. These data indicate that the induction of H1(0) and some H1 variants is an early event after TSH stimulation and may thus be related to the functional differentiation of FRTL-5 cells.

Animals↗