Search PubMed⌕ Search

Biomedical subjects

E Iafrate

Publications and source records attributed to E Iafrate.

4 recordsLinked to original sources
PubMed1998

Improved efficacy and enlarged spectrum of activity of a novel anthracycline disaccharide analogue of doxorubicin against human tumor xenografts.

On the basis of a structure-activity study of a new series of anthracycline disaccharides, we recently identified a doxorubicin analogue (MEN 10755) with a promising antitumor activity. In the present study, to better support the pharmacological interest of MEN 10755, we extended the preclinical evaluation of antitumor efficacy to a large panel of 16 human tumor xenografts, which originated from different clinicopathological types. Tumors with typical multidrug-resistant phenotype were excluded because MEN 10755 was found unable to overcome resistance mediated by transport systems. In the doxorubicin-responsive series, MEN 10755 exhibited a higher activity in three of five tumors, as documented by a more marked tumor growth inhibition and an increased value of log-cell kill. In the series of doxorubicin-resistant tumors, MEN 10755 was found effective in 6 of 11 tumors (1 breast, 3 lung, and 2 prostate carcinomas). The overall response rates were 31% and 69% for doxorubicin and MEN 10755, respectively. The improvement in drug efficacy was also supported by a substantial increase in the long-term survivor rate of animals implanted with responsive tumors. Most of the tumors refractory to doxorubicin and responsive to MEN 10755 were characterized by overexpression of the antiapoptotic protein Bcl-2. In one of these tumors (MX-1 breast carcinoma), we examined the ability of MEN 10755 to induce phosphorylation of Bcl-2 after a single treatment with therapeutic doses. The results indicated that, unlike doxorubicin, MEN 10755 induced protein phosphorylation. A similar modification was produced by Taxol, which is known to be very effective against the tumor. The correlation between drug efficacy and Bcl-2 phosphorylation may underly a peculiar feature related to improvement of efficacy of the disaccharide analogue. In conclusion, the present study supports some favorable features of the novel doxorubicin analogue in terms of both efficacy and tolerability with comparison to doxorubicin, although the improvement is somewhat tumor- and schedule-dependent.

Animals↗
PubMed1995

5-Iodo-2'-deoxy-L-uridine and (E)-5-(2-bromovinyl)-2'-deoxy-L-uridine: selective phosphorylation by herpes simplex virus type 1 thymidine kinase, antiherpetic activity, and cytotoxicity studies.

5-Iodo-2'-deoxy-L-uridine (L-IdU) and (E)-5-(2-bromovinyl)-2'-deoxy-L-uridine (L-BVdU) have been prepared and found to inhibit herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) with activities comparable to those of their analogs with the natural D-sugar configuration. The mechanism of inhibition is purely competitive for L-IdU (Ki = 0.24 microM) and mixed-type for L-BVdU (Ki = 0.13 microM). High performance liquid chromatographic analysis of the reaction products demonstrated that the viral enzyme phosphorylates both L-enantiomers to their corresponding monophosphates with efficiency comparable to that for D-enantiomers. Neither L-enantiomer inhibits the human cytosolic TK. In contrast to their D-enantiomers, L-IdU and L-BVdU have no effect on human thymidylate synthase, either in HeLa cells or in TK-deficient HeLa cells transformed with the HSV-1 TK gene. Both L-enantiomers (i) have no effect on HeLa cell growth, (ii) are 1000-fold less cytotoxic toward TK-deficient HeLa cells transformed with the HSV-1 TK gene than are their D-enantiomers, (iii) in contrast to their D-enantiomers, are fully resistant to hydrolysis by nucleoside phosphorylase, and, (iv) in spite of their much lower cytotoxicity, most probably due to the very low affinity of L-BVdU monophosphate and L-IdU monophosphate for thymidylate synthase, are only 1 or 2 orders of magnitude less potent than their D-enantiomers in inhibiting viral growth, with potency comparable to that of acyclovir.

Antineoplastic Agents↗
PubMed1989

In vivo and in vitro growth of SCLC cells derived from biopsies.

In order to increase the availability of SCLC cells derived from biopsies, in vivo and in vitro growth methods were investigated. The cells grown in both conditions were periodically monitored for reactivity with 2 monoclonal antibodies (MAbs): MLuC1 directed against SCLC cells and IM1 which recognizes the class II antigen on activated lymphocytes and macrophages. About 50% of the 28 analyzed SCLC specimens were found to proliferate in one or both systems. The in vitro-grown cells exhibited the same heterogeneity found in the original cell suspensions and moreover, in some cases only normal cells were recovered after several in vitro passages. From the subcutaneous transplanted tumors a large number of MLuC1-positive tumor cells could easily be recovered, thus indicating the validity of the in vivo methodology. The MBr1 MAb, directed against an epithelial antigen, was found to react with about 50% of the 26 tested tumors, mainly those which demonstrated in vivo and/or in vitro growth capacity. These data suggest that only some tumors, presumably with peculiar biological characteristics, can efficiently grow in these artificial systems.

Adult↗