New aldehyde and vinylsulfone proteasome inhibitors for targeted melanoma therapy.

The proteasome is a promising target in cancer therapy. However, it is ubiquitous and its inhibitors cause side effects. To target melanoma cells we synthesized new peptide aldehyde and vinylsulfone inhibitors of the proteasome conjugated to the melanin-targeting ligand (MTL) derived from radiotracer [(123)I]-N-(2-diethylaminoethyl)benzamide ([(123)I]BZA) or [(125)I]-N-(4-dipropylaminobutyl)-4-iodobenzamide ([(125)I]BZ18).

First preclinical imaging of primary cartilage neoplasm and its local recurrence using 99mTc-NTP 15-5 radiotracer.

Unlabelled: This study on a rat model of grade II chondrosarcoma aimed to determine whether the radiotracer N-(triethylammonium)-3-propyl-[15]ane-N5 radiolabeled with (99m)Tc ((99m)Tc-NTP 15-5), which binds to cartilage proteoglycans, has pathophysiologic validity for in vivo imaging of cartilage tumoral tissue.

Methods: We used 2 experimental approaches with the Swarm chondrosarcoma rat model: that is, a primary paratibial location and local recurrence after intralesional curettage. (99m)Tc-NTP 15-5 scintigraphy and (99m)Tc-hydroxymethylenediphosphonate ((99m)Tc-HMDP) scanning were performed at regular intervals during 50 d after tumor implantation in a paratibial location (primary model; n = 12 animals) and after intralesional curettage in a femoral condyle location (recurrence model; n = 9 animals).

Synthesis, radiosynthesis, and biological evaluation of new proteasome inhibitors in a tumor targeting approach.

Proteasome inhibition is a new strategy in cancer therapy. We synthesized three new peptide aldehyde inhibitors linked to the benzamide derivative structure to use their cytotoxic activity against malignant melanoma cells. Of these, 10 displayed the highest cytotoxicity (0.

A methionine-free diet associated with nitrosourea treatment down-regulates methylguanine-DNA methyl transferase activity in patients with metastatic cancer.

Background: Methionine (MET) depletion used in association with chemotherapy improves the therapeutic index in animal models. This potentiating effect may be due to tumor cell sensitization to chloroethylnitrosoureas through their MET dependency and the down-regulation of O6- methylguanine-DNA methyltransferase (MGMT). Our purpose was to evaluate the impact of the association of a dietary MET restriction with nitrosourea treatment on MGMT activity in peripheral blood mononuclear cells (PBMCs).

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.

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.

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.

Simulation of neutron interactions at the single-cell level.

We recently reported that the exposure of cancer cells to 14 MeV neutrons at a very low dose rate (0.8 mGy min(-1)) produced a marked increase in cell killing at 5 cGy, followed by a plateau in survival and chromosomal damage. Simulation of the energy deposition events in irradiated cells may help to explain these unusual cell responses.

Comparisons of carboplatin and cisplatin as potentiators of 5-fluorouracil and radiotherapy in the mouse L1210 leukaemia model.

Background: Carboplatin (CBDCA), an analogue of cisplatin (CDDP), has synergistic antitumour activity in combination with 5-fluorouracil (5-FU) and radiotherapy and is better tolerated than CDDP by patients. In an in vivo model, we evaluated the doses of CBDCA and CDDP required to obtain, in these combinations, equal curative effects.

Materials And Methods: Groups of 6-week-old B6D2F1 mice were injected with L1210 leukaemia.

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.