IRC-083927 is a new tubulin binder that inhibits growth of human tumor cells resistant to standard tubulin-binding agents.

Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site.

Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex.

A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Galphas), (b) calcium release (Galphaq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Galphao/i and Galphaq).

BN80927: a novel homocamptothecin that inhibits proliferation of human tumor cells in vitro and in vivo.

BN80927 belongs to a novel family of camptothecin analogs, the homocamptothecins, developed on the concept of topoisomerase I (Topo I) inhibition and characterized by a stable seven-membered beta-hydroxylactone ring. Preclinical data reported here show that BN80927 retains Topo I poisoning activity in cell-free assay (DNA relaxation) as well as in living cells, in which in vivo complexes of topoisomerase experiments and quantification of DNA-protein-complexes stabilization, have confirmed the higher potency of BN80927 as compared with the Topo I inhibitor SN38. In addition, BN80927 inhibits Topo II-mediated DNA relaxation in vitro but without cleavable-complex stabilization, thus indicating catalytic inhibition.

A novel B-ring modified homocamptothecin, 12-Cl-hCPT, showing antiproliferative and topoisomerase I inhibitory activities superior to SN-38.

We report the synthesis and pharmacological evaluation of a novel homocamptothecin (hCPT) derivative, 12-Cl-hCPT, which contains a seven-membered beta-hydroxylactone in place of the conventional six-membered alpha-hydroxylactone found in camptothecin (CPT) and bears a chloro substituent at position 12. The capacity of 12-Cl-hCPT to inhibit DNA topoisomerase I was compared with that of SN-38, the active metabolite of the clinically used antitumour prodrug CPT-11. In the DNA relaxation assay, 12-Cl-hCPT proved to be slightly more potent than SN-38 at stimulating the formation of nicked plasmid DNA molecules.

The homocamptothecin BN 80915 is a highly potent orally active topoisomerase I poison.

BN 80915, a lead compound of the homocamptothecin (hCPT) family, has entered clinical trials. BN 80915 is a difluoro-hCPT where the six-membered alpha-hydroxylactone ring of camptothecin (CPT) is replaced by a seven-membered beta-hydroxylactone ring. Preclinical data reported here show that in spite of the modification to the crucial E-ring of CPTs, BN 80915 retains topoisomerase I poisoning activity as shown in living HT29 cells as well as in cell-free assays, where BN 80915 always performs better than SN-38 or TPT.

Topoisomerase I-mediated antiproliferative activity of enantiomerically pure fluorinated homocamptothecins.

Homocamptothecin (hCPT) is an E-ring modified camptothecin (CPT) analogue bearing a methylene spacer between the alcohol and carboxyl functions of the CPT lactone. Combining pronounced inhibitory activity of topoisomerase I (Topo I) with enhanced plasma stability, hCPT constitutes an attractive template for the elaboration of new anticancer agents. Fluorinated hCPT analogues, prepared in enantiomerically pure form, were assayed by their stimulation of Topo I-mediated DNA cleavage.

Homocamptothecin, an E-ring-modified camptothecin analogue, generates new topoisomerase I-mediated DNA breaks.

Homocamptothecin (hCPT) contains a seven-membered beta-hydroxylactone in place of the conventional six-membered alpha-hydroxylactone ring found in camptothecin and its tumor active analogues, including topotecan and irinotecan. The homologation of the lactone E-ring reinforces the stability of the lactone, thus reducing considerably its conversion into a carboxylate form which is inactive. We have recently shown that hCPT is much more active than the parent compound against a variety of tumor cells in vitro and in xenograft models, suggesting that a highly reactive lactone is not essential for topoisomerase I-mediated anticancer activity [Lesueur-Ginot et al.

BN 80927: a novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II.

BN 80927, a novel homocamptothecin derivative, inhibits both topoisomerase I and topoisomerase II mediated DNA relaxation and shows pronounced cytotoxicity against HT29, SKOV-3, DU145 and MCF7 human tumor cell lines.

Flow cytometric monitoring of anthracycline accumulation after anti-neoplastic ether phospholipid treatment.

Ether phospholipids are new anti-neoplastic drugs that have been found active against a variety of tumor cell lines, including drug-resistant sublines. We have characterized the antiproliferative activity of three ether phospholipids, i.e.

New antineoplastic aza-phospholipids - synthesis, in-vitro cytotoxicity and differential cellular-sensitivity against 70 human tumor-cell lines.

The in vitro cytotoxicity and differential cellular sensitivity of three new synthetic anti-neoplastic aza-phospholipids has been determined in the National Cancer Institute's (NCI) primary antitumor drug screen. Based on a disease-oriented strategy, this screen incorporates seventy human cell lines representing leukemia, ovarian, brain, melanoma, colon, renal, lung, prostate and breast cancers. The analysis of the GI50 values obtained for each aza-derivative has revealed a differential cellular sensitivity among the cell lines examined.

Tumor cell kinetics following long-term treatment with antineoplastic ether phospholipids.

Ether phospholipids are analogs of the naturally occurring 2-lysophosphatidylcholine that have been reported to have selective in vitro/in vivo antitumor activity. Their antiproliferative effect has been found against a variety of animal and human tumor cell lines. We have characterized the cytostatic activity of four ether phospholipids, the methoxy-substituted edelfosine (ET-18-OCH 3), the thio-derivative ilmofosine (BM 41.

Immunomodulatory activity of two new aza alkyl phospholipid antineoplastic drugs.

The present work reports the modulation of immunocompetent cell functions by two aza alkyl phospholipids (AAP), BN 52205 and BN 52211. Each compound was compared with 1-O-octadecyl-2-O-rac-glycero-3-phosphocholine (ET-18-OCH3) and/or three drugs used for cancer treatment, i.e.

Evaluation of combinations of antineoplastic ether phospholipids and chemotherapeutic drugs.

Combinations of drugs are used clinically for the therapeutic advantages they may provide over single agents. We have studied the cytotoxic interaction between four either phospholipids ET-18-OCH3, BM 41.440, BN 52205 and BN 52211, and several chemotherapeutic drugs (ADM, CDDP, VLB, VP-16, MMC, BLM and MTX) on two human tumor cell lines, A427 (lung) and HT29 (colon).

Effect of serum concentration on the cytotoxicity and sister chromatid exchange induction by a chemical carcinogen and by a diesel particulate extract in V79 hamster cells.

The role of serum concentration on the cytotoxicity and on the sister chromatid exchange (SCE)-induction by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and by a diesel particulate extract (DPE), a complex mixture, has been carried out on V79 cells. An increase of the serum concentration in the medium decreases the toxicity of these chemicals, and especially when they are dispersed first in serum. Although no influence of serum concentration on the number of spontaneous SCEs occurring in control cells has been observed, the increase of serum concentration leads to a decrease in SCE's induction in treated cells.

Tumour-initiating activities of dihydrodiols of dibenz[a,c]anthracene.

The tumor-initiating activities of dibenz[a,c]anthracene (DBA) and of the related trans-1,2-, 3,4- and 10,11-dihydrodiols have been examined on mouse skin subsequently promoted with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The 1,2- and 10,11-dihydrodiols were active and were more active than equivalent doses of either the parent hydrocarbon or the 3,4-dihydrodiol. The data are discussed in relation to possible mechanisms that may be involved in the metabolic activation of DBA.

The uptake and release of benzo[a]pyrene and benzo[e]pyrene in vitro by Syrian hamster embryo cells as a function of serum concentration.

A quantitative study on the in vitro uptake of benzo[a]pyrene (B[a]P) and benzo[e]pyrene (B[e]P) by Syrian hamster embryo cells and the induction of sister chromatid exchange (SCE) has been carried out. The amounts of B[a]P and B[e]P taken up by the cells decreases as does the induction of SCEs by B[a]P when the concentration of serum in the culture medium increases. It appears that serum prevents (B[a]P or B[e]P uptake.