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Biomedical subjects

F Formelli

Publications and source records attributed to F Formelli.

At least 73 records · Page 4Linked to original sources
PubMed1987

Pharmacokinetics of 4'-deoxy-4'-iodo-doxorubicin in plasma and tissues of tumor-bearing mice compared with doxorubicin.

It has been reported that 4'-deoxy-4'-iodo-doxorubicin (4'-deoxy-4'-I-DX) displays, on experimental tumors, a spectrum of activity comparable to that of doxorubicin, is active when administered orally, is not cardiotoxic, and is cytotoxic to doxorubicin-resistant cells. We have investigated by high-performance liquid chromatography the pharmacokinetics of this drug in comparison with doxorubicin by treating mice bearing colon 38 adenocarcinoma with equal doses of the two drugs i.v. 4'-Deoxy-4'-I-DX, unlike doxorubicin, is transformed into several metabolites. The 13-dihydro derivative is the major metabolite found; in tumor and in all the organs it accounts for 4-7% of the total fluorescent area under the curve, whereas in plasma and liver it accounts for 15 and 34%, respectively. 4'-Deoxy-4'-I-DX disappears from plasma with a terminal half-life of 5 h, which is half the terminal half-life of doxorubicin (11 h), and its efficiency of absorption after oral administration is 27%. Tissue concentrations of 4'-deoxy-4'-I-DX are initially highest in lung and spleen, whereas those of doxorubicin are highest in liver and kidney. 4'-Deoxy-4'-I-DX levels are higher than those of doxorubicin in tumor, spleen, lung, small intestine, brain, pancreas, and ovaries whereas they are similar in heart, liver, kidney, and bone marrow. The rate of elimination of the new analogue is higher than that of doxorubicin from the tumor and all the organs investigated except the liver. The area under the curve of 4'-deoxy-4'-I-DX is similar to that of doxorubicin in tumor and spleen, whereas it is three times lower in heart. This may explain the lack of cardiotoxicity of this new analogue, which is equiactive and equitoxic with doxorubicin on the experimental system tested.

Adenocarcinoma↗
PubMed1986

Comparative pharmacokinetics and metabolism of doxorubicin and 4-demethoxy-4'-O-methyldoxorubicin in tumor-bearing mice.

It has been reported that 4-demethoxy-4'-O-methyldoxorubicin (4-dm-4'-O-methylDX) is more potent than doxorubicin (DX), equally active in some murine leukemias and solid tumors, and almost devoid of cardiotoxicity. We used HPLC to investigate the metabolism and the disposition of this drug in comparison with DX in mice bearing colon 38 adenocarcinoma SC and treated with IV doses of the two drugs that were equiactive and equitoxic (4-dm-4'-O-methylDX 1 mg/kg; DX 10 mg/kg). 4-Dm-4'-O-methylDX was metabolized to a polar metabolite, presumably 4-demethoxyDX, which was eliminated more slowly than the parent drug from all the organs and accounted for 25%-50% of total fluorescence; traces of two metabolites less polar than the parent drug (2% of total fluorescence) were found only at early times in the liver. In DX-treated mice traces of doxorubicinol (1%-3% of total fluorescence) were found in tumor and organs, and two aglycones were detected only at early times in the liver. In plasma both drugs declined biexponentially and 4-dm-4'-O-methylDX was eliminated slightly faster than DX. The rate of elimination of the new analogue from lung, kidney, spleen, and small intestine was faster than that of DX; in heart and liver 4-dm-4'-O-methylDX was detectable for only up to 24 h, while DX was detectable for up to 7 days. In the tumor the kinetics and the elimination patterns of the two drugs were similar. The distribution of 4-dm-4'-O-methylDX, as a percentage of the administered dose, was 1.3-2 times higher than that of DX in the organs and 3 times higher in the tumor, which suggests an improved selectivity of the new analogue for the tumor compared with DX.

Animals↗
PubMed1986

Characterization of a doxorubicin-resistant murine melanoma line: studies on cross-resistance and its circumvention.

A B16 mouse melanoma cell line resistant to doxorubicin was obtained by continuous in vitro exposure to the drug. The ID50 for this line was 200 times higher than that for the parental cell line. The resistant cell line had some biological characteristics similar to those of the sensitive parental cell line, like saturation density and protein content. Differences were found in doubling time which was longer, cloning efficiency which was lower and DNA content which was higher in the resistant as compared to the parental line. Intracellular distribution of doxorubicin was also different having a nuclear-cytoplasmic ratio higher in sensitive than in resistant cells. Melanin content was an unstable feature in the sensitive cell line, whereas melanin was always present in resistant cells. Resistance to doxorubicin was maintained during 50 in vitro passages in the absence of the drug. Cross-resistance was found with vincristine and other anthracyclines, like daunorubicin and 4'-epi-doxorubicin but not with cis-platinum, and a new doxorubicin derivative, 4'-deoxy-4'-iodio-doxorubicin. The B16 line showed a lower resistance index to 4'-deoxy-doxorubicin and 4-demethoxy-daunorubicin (30 and 3 respectively), as compared to doxorubicin. Doxorubicin-resistance was partially circumvented by pretreatment of resistant cells with verapamil, a calcium chelating agent, and by trifluoperazine, a calmodulin-antagonist.

Animals↗
PubMed1986

In vivo characterization of a doxorubicin resistant B16 melanoma cell line.

A doxorubicin-resistant line of B16 melanoma (B16VDXR) was obtained in vitro by continuous exposure to increasing concentrations of doxorubicin of an in vitro line (B16V) derived from the in vivo transplanted B16 melanoma. When injected s.c. into mice, B16VDXR exhibited histological features, metastatic behaviour, doubling time and tumourigenic potential similar to those of the parental B16V line. Tumours obtained by implantation of B16VDXR, however, had longer latency and permitted a longer survival time than B16V and had, as in vitro, a higher DNA content. After i.v. inoculation, B16VDXR cells had lower lung colonizing capability compared to B16V. B16V and B16VDXR had significantly lower metastatic potential compared to the B16 melanoma from which they derived. Doxorubicin treatment significantly delayed the growth of B16 and B16V transplanted s.c. and increased the life span of animals bearing B16V. B16VDXR was resistant to doxorubicin treatment when the in vitro resistance index was greater than 100. While the doxorubicin-resistance phenotype was stable in vitro for 50 passages, in vivo the resistance phenotype was lost in 5 passages and tumours grown from s.c. inocula of mixtures of similar percentages of sensitive and resistant cells behaved as sensitive tumours. Cis-diamminedichloroplatinum (II), although marginally active in animals bearing B16V, was highly effective in B16VDXR bearing animals, suggesting a collateral cis-diamminedichloroplatinum (II) sensitivity of the B16VDXR line. After a single i.v. administration, doxorubicin reached initially, in the B16VDXR line, levels similar to those found in the B16 and B16V lines, but its release was faster from the resistant line in comparison with the sensitive ones. Doxorubicin-resistance was not overcome by more frequent treatments with doxorubicin. This doxorubicin-resistant tumour line obtained in vitro and used as a first in vivo transplant, may be a suitable metastaizing model for in vivo study of the mechanisms of resistance and of collateral sensitivity and for screening new drugs.

Animals↗
PubMed1984

Effect of medroxyprogesterone acetate and of some antiinflammatory agents on mouse erythroleukemia cell differentiation.

The effects of medroxyprogesterone acetate (MPA) on differentiation were examined using mouse erythroleukemia (MEL) cells and compared with those of antiinflammatory agents. MPA at low doses (10(-6) - 10(-7)M) induced 10-15% cells to differentiate, whereas high doses (10(-4) - 10(-5)M) caused a 30% inhibition of dimethylsulfoxide (DMSO)-induced differentiation. Dexamethasone (10(-4) - 10(-8)M), a steroid antiinflammatory agent, significantly inhibited (77-70%) DMSO-induced differentiation, whereas indomethacin, aspirin, flurbiprofen and BW755c (non steroid antiinflammatory agents) at the same concentrations had no effect. If added 24 h before DMSO, the inhibitory effects of MPA and dexamethasone increased to 65% and 95%, respectively, whereas indomethacin (10(-5)M) caused only a 30% inhibition and the other drugs were inactive. None of these antiinflammatory agents affected differentiation when used without DMSO. MPA and dexamethasone inhibitory effects on DMSO-induced differentiation did not seem to be mediated through the inhibition of the synthesis of prostaglandins, since non-steroid prostaglandin inhibitors were slightly active only when added 24 h before DMSO.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1983

Correlation between inhibitory effect on prolactin secretion and antitumor activity of new ergoline compounds on DMBA-induced tumors in rats.

Five recently synthesized (355/1057, 355/1000, 355/1101, 355/1138 and FCE 21336) and 4 well-known (bromocriptine, metergoline, 1-demethylmetergoline and pergolide) prolactin-lowering ergoline derivatives and 1 ergoline (nicergoline) without antiprolactin activity were tested against 7-12-dimethyl-benzanthracene (DMBA)-induced mammary carcinomas in rats. Nicergoline did not show any activity, while the other compounds, tested at doses inhibiting prolactin secretion, proved active against established tumors and on the onset of new tumors. The activity of 3 of the new ergolines (355/1000, 355/1057 and FCE 21336) and of bromocriptine and pergolide was also tested at different oral doses and was correlated with serum prolactin levels 24 hr after the last dose. All the compounds proved highly effective, inducing 50-60% regression of the initial tumors. The inhibition of serum prolactin levels was dose-related and, for all the compounds tested except bromocriptine, a good correlation was found between doses administered and complete tumor remissions.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

Fluorescence assays and pharmacokinetic studies of 4'-deoxydoxorubicin and doxorubicin in organs of mice bearing solid tumors.

The pharmacokinetic of 4'-deoxydoxorubicin, a new analog of doxorubicin, was compared with that of its parent compound in mice treated with equal and equiactive doses. The levels of total fluorescence due to the initial drugs and to metabolites were determined in tissue extracts by fluorometry. 4'-Deoxydoxorubicin reached the same tissue levels as doxorubicin in all the organs tested except in spleen and lung, where a higher peak was found in the animals treated with the new analog. The rate of elimination of 4'-deoxydoxorubicin from the organs tested was higher than that of doxorubicin.

Animals↗
PubMed1979

Fluorescence assay of tissue distribution of 4-demethoxydaunorubicin and 4-demethoxydoxorubicin in mice bearing solid tumors.

The tissue distribution of 4-demethoxydaunorubicin and 4-demethoxydoxorubicin was studied in comparison with that of their patient compounds, daunorubicin and doxorubicin, in mice bearing transplanted tumors. The doses administered were equal or equitoxic to those of their parent compounds. The levels of total fluorescence due to initial drugs and metabolites were determined on tissue extracts by fluorometry. After administration of equal doses of daunorubicin and 4-demethoxydaunorubicin, the calculated Cxt values of 4-demethoxydaunorubicin equivalents were higher than those for daunorubicin in all the organs tested except the heart. In animals treated with equitoxic doses, lower 4-demethoxydaunorubicin levels were found in all the organs tested. In mice treated with equitoxic doses of doxorubicin and 4-demethoxydoxorubicin, 4-demethoxydoxorubicin reached higher drug concentrations than doxorubicin in spleen and liver, whereas in all the other organs tested lower drug levels were found. The rate of drug disappearance from organs was slower in animals treated with 4-demethoxyderivatives than in those treated with their parent drugs.

Animals↗
PubMed1978

Enhancement of the antitumor activity of adriamycin by Tween 80.

This paper describes the effect of Tween 80 on the antitumor activity and on the distribution of adriamycin in mice. The dilution of adriamycin in a 10% water solution of Tween 80 produced a significant increase of the antitumor activity in mice against ascites tumors (L 1210 leukemia), disseminated leukemias (transplanted leukemias originally induced by Gross leukemai virus and Moloney leukemia virus), and solid tumors (Sarcoma 180, MS-2 sarcoma). In all these experiments the drug was administered i.v., according to different schedules. Higher antitumor activity at the optimal dose and an increase of activity at lower doses were observed in different experimental systems. Toxicity was also slightly enhanced. Tissue distribution was studied in normal mice and in tumor-bearing mice (Gross leukemia and MS-2 sarcoma). In animals give i.v. adriamycin diluted in 10% Tween 80 there was a higher drug concentration in spleen, lung and kidney than there was in mice given the drug in a water solution. In all the other organs examined (heart, liver, small intestine) and in the MS-2 tumor tissue, no significant increase was observed. In L1210 leukemia-bearing mice, i.p. treatment with adriamycin diluted in 10% Tween 80 resulted in a significantly higher toxicity than that which resulted from treatment with adriamycin in a wa ter solution; no increase of antitumor activity was observed.

Animals↗
PubMed1978

Effects of adriamycin on DNA synthesis in mouse and rat heart.

Adriamycin induces an inhibition of DNA synthesis in mouse tissues within one hr after treatment. While the effects are short-lived in liver and small intestine, DNA synthesis in heart remains below control values for up to 7 days. After this period DNA synthesis in hearts of treated mice is elevated and remains above control values for as long as 4 weeks. Both 1-beta-D-arabinofuranosylcytosine and actinomycin D also induce inhibition of cardiac DNA synthesis soon after treatment; the effects of 1-beta-D-arabinofuranosylcytosine are over by the end of 24 hr while the effects of actinomycin D persist for at least 4 days. Actinomycin D treatment also induces an "over-shoot" of DNA synthesis in mouse heart. Adriamycin can induce a loss of prelabeled DNA from heart, although no pathological alterations are immediately obvious. The small intestine, however, shows extensive karyorrhexis. The initial effects on cardiac DNA synthesis occur in adrenalectomized animals, indicating that the effects are not mediated via the adrenal gland. We did find, however, that DNA synthesis in heart was sensitive to the effects of starvation. The results of this study indicate that inhibition of mouse heart DNA synthesis is not specific for Adriamycin and that the effects of Adriamycin in heart following a single treatment are long-lived.

Animals↗
PubMed1975

Synthesis and antitumor properties of new glycosides of daunomycinone and adriamycinone.

The synthesis of 4'-epi-daunorubicin and of 4'-epi-adriamycin was performed by condensation of 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-alpha-L-arabino-hexopyranosyl chloride with daunomycinone or the protected adriamycinone derivative 17, respectively. Both the alpha and beta anomers were obtained and characterized. All new compounds are biologically active in cultured cells and the alpha anomers display noticeable activity in experimental tumors in mice. Interestingly, 4'-epi-adriamycin (4) appears nontoxic to cultured heart cells up to a concentration of 5 mug/ml.

Aminoglycosides↗
PubMedDate not supplied

Tumors and dental and ocular abnormalities after treatment of infant rats with adriamycin.

In rats repeatedly treated subcutaneously as infants with adriamycin in 2 cycles of 4 treatments each, the induction of ocular and dental abnormalities and tumors was studied. Cataracts appeared from 18 to 26 days in 80% of CD rats treated with 1.15 mg/kg/day of adriamycin and from 28 to 104 days in 55% of Wistar-Lewis rats given 0.75 mg/kg/day adriamycin. Abnormal growth of incisors was observed in 30% of the CD rats and in 44% of the Wistar-Lewis rats. At lower doses, no such abnormalities were found. At about 1 year after treatment, 100% of the CD rats treated with 0.75 mg/kg/day adriamycin and about 60% of the Wistar-Lewis rats treated with 0.75 and 0.5 mg/kg/day adriamycin developed tumors, which were histologically classified.

Adenoma↗
PubMedDate not supplied

Chemoprevention of breast cancer with fenretinide (4-HPR): study of long-term visual and ophthalmologic tolerability.

BACKGROUND: Fenretinide (4-HPR) is a synthetic retinoid being clinically tested in the chemoprevention of different tumors and precancerous lesions. Though safer than many other retinoids in experimental models, in humans 4-HPR may induce adverse effects that mainly affect the eye and visual function. Such effects are thought to be caused by the reduction of plasma retinol levels, which occurs after administration of the retinoid. METHODS: A series of 826 women treated with 4-HPR was studied to quantify the incidence and temporal pattern of occurrence of visual (dark adaptation) and ophthalmologic complaints (ocular dryness, lacrimation, conjunctivitis or photophobia) and to investigate the possible association between their occurrence and plasma retinol levels. RESULTS: The cumulative incidence of visual complaints reached nearly 20% at 5 years. The occurrence of these symptoms was more frequent at the start of treatment. The probability of developing visual complaints was significantly higher in patients with lower plasma retinol concentrations following 4-HPR treatment. The cumulative incidence of ophthalmologic complaints was 8% at 5 years. The occurrence of these complaints was evenly distributed during treatment. Ophthalmologic complaints were not associated with a greater degree of reduction of plasma retinol concentrations, but rather with the patient's age, since symptomatic patients were generally older than asymptomatic patients. CONCLUSIONS: Visual and ophthalmologic complaints are common during 4-HPR treatment; their estimated 5-year cumulative incidence is close to 20% and 8%, respectively. However, the pattern of occurrence over time and the underlying mechanisms of these two types of complaints seem different.

Adult↗
PubMedDate not supplied

Chemoprevention trial of contralateral breast cancer with fenretinide. Rationale, design, methodology, organization, data management, statistics and accrual.

The Fenretinide (4-HPR) Breast Cancer Study is a randomized multicenter clinical trial originally designed and conducted by the investigators of the Istituto Nazionale Tumori of Milan. The study is sponsored by the National Cancer Institute of Bethesda and by the Italian National Research Council. The trial was designed to evaluate the effectiveness of the synthetic retinoid 4-HPR, at a dose of 200 mg per os every day for 5 years, in reducing the incidence of contralateral breast cancer in a population of patients previously operated on for breast cancer. Between 1987 and 1993, the Istituto Nazionale Tumori of Milan and 9 other collaborating Centers enrolled 2,972 women between the ages of 30 and 70 years who had been previously operated on for T1-T2 N- M0 breast cancer. This paper describes the rationale, design, methodology, organization, data management, statistics and accrual of the participating population.

Adult↗