Design, synthesis and preliminary biological evaluations of novel amphiphilic drug carriers.

The synthesis of a new fluorocarbon amphiphilic drug carrier is described. A polyfunctional amino acid endowed with a fluorocarbon chain and a sugar moiety providing the amphiphilic character constitutes the central element of this structure. A (14)C-radiolabelled acetyl group was grafted onto the third function and the bioavailability of this molecule was specified in mice after IV administration. This amphiphilic drug carrier exhibits a rapid and homogeneous distribution to the whole tissues and slow elimination half-lives (higher than one day) through a biliary excretion without any toxicity (no measured DL 50 for concentrations up to 500 mg/kg).

Cytotoxic effects of kinetin riboside on mouse, human and plant tumour cells.

The cytotoxicity of two plant hormone compounds, kinetin and kinetin riboside, was studied on tumour cells, by colony forming assay with increased amount of cytotoxic molecules. The concentration of inhibitor required to reduce cell growth to 50% was determined for these molecules. Kinetin riboside was shown to only act on M4 Beu human and B16 murine melanoma cells at low concentration (1.5 and 0.2 microM). On mice with leukaemia P388, this product has no effect on the tumour growth, and it appears to be toxic at the dose of 25 mg/kg. Kinetin riboside was also shown to have a cytotoxic effect on plant tumour cells (crown-gall).

Synthesis and pharmacokinetic profile of a quaternary ammonium derivative of chlorambucil, a potential anticancer drug for the chemotherapy of chondrosarcoma.

As a part of our targeting program based on the affinity of the quaternary ammonium moiety for cartilage, our objective was to develop more selective anticancer drugs towards chondrosarcoma that would concentrate in this malignant cartilaginous tissue and so improve the therapeutic index through a reduction of side effects. For this purpose we have synthesized and labeled with 14C a quaternary ammonium (QA) derivative of chlorambucil. Biological studies performed in rats showed that [14C]-CQA and [14C]-chlorambucil exhibited different pharmacokinetic profiles. The blood elimination of [14C]-CQA was faster than that of parent compound. [14C]-CQA was principally excreted by the fecal way. However, until 15 min after administration, levels of radioactivity were measured in cartilaginous tissues of rats given [14C]-CQA which was not the case for the rats which had received [14C]-chlorambucil. Although rates of radioactivity were quantified only during 15 min, these results prove that the functionalization of chlorambucil by a quaternary ammonium group allows the molecule to be carried selectively to cartilaginous tissues.

Synthesis and in vivo biodisposition of [14C]-quaternary ammonium-melphalan conjugate, a potential cartilage-targeted alkylating drug.

For the purpose of developing more selective anticancer drugs that would concentrate in the malignant cartilaginous tumors (chondrosarcomas), and so improve therapeutic index through a reduction of side effects, a quaternary ammonium (QA) conjugate of melphalan was synthesized and labeled with (14)C by linking the QA moiety to nitrogen mustard via an amide bond. Comparative pharmacokinetic study of [(14)C]-melphalan and its [(14)C]-QA conjugate conducted on rats showed that the two compounds were principally excreted by the urinary way. The blood elimination of the QA conjugate was faster than that of the melphalan. In the other hand a higher rate of radioactivity derived of [(14)C]-MQA was found in feces. In the biodisposition for most organs, no striking differences were found between melphalan and its QA conjugate except for cartilages which exhibited more higher radioactivity level. Amounts of radioactivity derived from [(14)C]-QA conjugates measured in cartilaginous tissues until 1 h after injection demonstrate that the introduction of a QA moiety on melphalan allows the molecule to be carried selectively to cartilaginous tissues. As the [(14)C]-QA conjugate is radiolabeled on the chloroethyl alkylating moiety, levels of radioactivity measured in the cartilaginous tissues results from unchanged compound or metabolite having kept the active group.

Differential effects of n-3 and n-6 polyunsaturated fatty acids on BRCA1 and BRCA2 gene expression in breast cell lines.

Current evidence strongly supports a role for the breast tumour suppressor genes, BRCA1 and BRCA2, in both normal development and carcinogenesis. In vitro observations reported that BRCA1 and BRCA2 are expressed in a cell cycle-dependent manner. Interestingly, differences in the actions of n-3 and n-6 polyunsaturated fatty acids have been observed: while the n-3 polyunsaturated fatty acids have been described to reduce pathological cell growth, the n-6 polyunsaturated fatty acids have been found to induce tumour proliferation. Here, we examined the expression of BRCA1 and BRCA2 in breast cell lines after treatment with polyunsaturated fatty acids. Real-time quantitative polymerase chain reaction determinations conclusively demonstrated increases in BRCA1 and BRCA2 mRNA expressions in MCF7 and MDA-MB 231 tumour cell lines after treatment with n-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid), but no variation was noticed with the n-6 polyunsaturated fatty acid (arachidonic acid). On the other hand, no variation of the expression of BRCA1 and BRCA2 mRNA was detected in MCF10a normal breast cell line treated by polyunsaturated fatty acids. The level of BRCA1 and BRCA2 proteins quantified by affinity chromatography remained unchanged in tumour (MCF7, MDA-MB 231) and normal (MCF10a) breast cell lines. We suggest the presence of a possible transcriptional or post-transcriptional regulation of BRCA1 and BRCA2 after n-3 polyunsaturated fatty acid treatment in breast tumour cells.

Synthesis and in vitro evaluation of quaternary ammonium derivatives of chlorambucil and melphalan, anticancer drugs designed for the chemotherapy of chondrosarcoma.

To enhance affinity for malignant cartilaginous tumors (chondrosarcomas), quaternary ammonium (QA) conjugates of chlorambucil and melphalan were prepared by linking the QA moiety to nitrogen mustards via an amide bond. They exhibited closely similar and sometimes more favorable values than their parent compounds. In the cell lines tested, the two QA conjugates displayed appreciable cytotoxicity, the QA conjugate of chlorambucil even showing an enhanced efficiency against chondrosarcoma compared with chlorambucil.

Synthesis and preliminary biological assessments of RGD bearing biocompatible telomers.

Work reported herein deals with the synthesis and preliminary biological assessments of a new class of biocompatible telomeric carriers bearing peptidic RGDSK sequences as tumor cell targeting and tyrosine moieties labelled with 125I as in vivo probe. The radioactivity levels obtained in several tissues, after the intravenous injections of these telomers in mice bearing grafted B16 syngenic melanoma showed that the addition of a RGD residue to a telomeric structure confers it an increased affinity for the highly vascularized zone surrounding the tumor.

Presence of BRCA1 and BRCA2 proteins in human milk fat globules after delivery.

We evaluated BRCA1 and BRCA2 oncosuppressor protein expression in 26 milk samples in women just after delivery. The quantification of BRCA1 and BRCA2 proteins was performed in isolated milk fat globules using an affinity chromatography strategy. The amounts of BRCA1 and BRCA2 proteins were found to be similar. We explained the presence of BRCA1 and BRCA2 proteins in human milk fat globules by the fact that they are formed by exocytosis of lipids from epithelial cells of the mammary gland and are enveloped by plasma membrane from the apical part of the milk-secreting cells. This raises the possibility that BRCA1 and BRCA2 proteins are a protective response to proliferation and play a possible role in newborn nutrition.