La molécule DMAPT

Le DMAPT est autrement appelé le parthenolide...

Nuclear factor-kappaB (NF-kappaB), activated in multiple myeloma (MM) cells by microenvironmental cues, confers resistance to apoptosis. The sesquiterpene lactone parthenolide targets NF-kappaB. However, its therapeutic potential in MM is not known.

EXPERIMENTAL DESIGNS: We explored the effects of parthenolide on MM cells in the context of the bone marrow microenvironment.

RESULTS: Parthenolide inhibited growth of MM cells lines, including drug-resistant cell lines, and primary cells in a dose-dependent manner. Parthenolide overcame the proliferative effects of cytokines interleukin-6 and insulin-like growth factor I, whereas the adhesion of MM cells to bone marrow stromal cells partially protected MM cells against parthenolide effect. In addition, parthenolide blocked interleukin-6 secretion from bone marrow stromal cells triggered by the adhesion of MM cells. Parthenolide cytotoxicity is both caspase-dependent and caspase-independent. Parthenolide rapidly induced caspase activation and cleavage of PARP, MCL-1, X-linked inhibitor of apoptosis protein, and BID. Parthenolide rapidly down-regulated cellular FADD-like IL-1beta-converting enzyme inhibitory protein, and direct targeting of cellular FADD-like IL-1beta-converting enzyme inhibitory protein using small interfering RNA oligonucleotides inhibited MM cell growth and lowered the parthenolide concentration required for growth inhibition. An additive effect and synergy were observed when parthenolide was combined with dexamethasone and TNF-related apoptosis-inducing ligand, respectively.

CONCLUSION: Collectively, parthenolide has multifaceted antitumor effects toward both MM cells and the bone marrow microenvironment. Our data support the clinical development of parthenolide in MM therapy.

Conclusion : Collectivement, le parthenolide a différents effets sur les cellules du Myélome multiple et sur le microenvironnement de la moelle épinière. nos données supportent le développement clinique duparthenolide comme thérapie.

A new, easily ingested form of a compound that has already shown it can attack the roots of leukemia in laboratory studies is moving into human clinical trials, according to a new article by University of Rochester investigators in the journal, Blood.

Une nouvelle molécule facilement ingérable qui a déja démontré son pouvoir de s'attaquer aux racines de la leucémie en laboratoire sera l'objet d'études cliniques selon le journal Blood.


The Rochester team has been leading the investigation of this promising therapy on the deadly blood cancer for nearly five years. And to bring it from a laboratory concept to patient studies in that time is very fast progress in the drug development world, said Craig T. Jordan, Ph.D., senior author of the Blood article and director of Translational Research for Hematologic Malignancies at the James P. Wilmot Cancer Center, at the University of Rochester Medical Center.

L'équipe de Rochester a conduit la recherche sur cette thérapie prometteuse contre le cancer du Et de l'avoir amener du laboratoire à la clinique en 5 ans représente un temps exceptionnelement court dans le monde du médicament.

Clinical trials are expected to begin in England by the end of 2007. Investigators expect to initially enroll about a dozen adult volunteers who've been diagnosed with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or other types of blood or lymph cancers, Jordan said.

Les essais cliniques vont commencer en Angleterre à la fin de 2007.
Les chercheurs s'attendent à enroller une douzaine d'adulte volontaires qui ont diagnostiqué avec l'ALL ou d'autres types de cancers du ou des nodules lymphatiques.

Under development is dimethylamino-parthenolide (DMAPT), a form of parthenolide (PTL) that is derived from a daisy-like plant known as feverfew or bachelor's button. DMAPT is a water-soluble agent that scientists believe will selectively target leukemia at the stem-cell level, where the malignancy is born. This is significant because standard chemotherapy does not strike deep enough to kill cancer at the roots, thus resulting in relapses. Even the most progressive new therapies, such as Gleevec, are effective only to a degree because they do not reach the root of the cancer.

Le DAMPT sopus développement est un agent soluble dans l'eau que les scientifiques croient avoir le pouvoir de cibler la leucémie au niveau des cellules-souches ou la maladie est née. C'est significatif puisque les médicaments actuels ne frappent pas assez profondément pour tuer la racine de la maladie et donc le malade rechute. Même les thérapies les plus nouvelles, comme le Gleevec, sont efficace seulement à un certain degré parce qu'elles ne peuvent pas atteindre la racine du mal.

DMAPT appears to be unique. It's mechanism of action is to boost the cancer cell's reactive oxygen species -- which is like pushing the stress level of the cell over the edge -- to the point where the cell can no long protect itself and dies, said Monica L. Guzman, Ph.D., the lead researcher on the DMAPT project and a senior instructor at the University of Rochester Medical Center.

Le DAMPT est unique. Son mécanisme d'action est de booster le ROS (reactive oxygenen stress) ce qui est comme pousser le niveau de stress de la cellule cancéreuse d'une façcon qu'elle ne peut controler et ou elle se suicide.

Leukemia is different from most cancers and particularly hard to eradicate because leukemia stem cells lie dormant. Standard cancer treatments are designed to seek out actively dividing cells. But in studies so far, DMAPT can kill both dormant cells and cells that are busy dividing, Guzman said

La leucémie est différente des autres cancers et particulièrenment difficille à éradiquer à cause des cellules souches dormantes. Le traitement standart du cancer est réputé s'attaquer à la division des cellules. Mais dans les études, DMAPT a tué les cellules qui se divisent et les cellules dormantes.

Rochester investigators looked at whether DMAPT could eliminate leukemia in donated human cells, and in mice and dogs. In all cases, DMAPT induced rapid death of AML stem and progenitor cells, without harming healthy blood cells.

Les chercheurs de Rochester ont regardé si le DMAPT pourrait éliminer la leucémie humaine ches les souris et les chiens. Dans tous les cas, le DMAPT a induit une mort rapide des cellules AML et de leurs cellules-filles sans endommager les cellules saines.

DMAPT also has shown potential as a treatment for breast and prostate cancer, melanoma, and multiple myeloma, Guzman said, although those studies have only been conducted in cell cultures to date.

LeDMAPT a montré aussi un potentiel de traitement pour le cancer du , de la , de la du myélome multiple . Même si ces études ont été faites seulement en laboratoire jusqu'ici.

"Once we begin seeing evidence from the clinical trials, it will give us more insight into the pharmacological properties of DMAPT and it will be easier to figure out its potential for other cancers," Guzman said.

In addition to the studies of DMAPT, Guzman and Jordan also reported in the same issue of Blood on another new type of leukemia drug known as TDZD-8. Although this agent is at a much earlier stage of development, it also shows the ability to kill leukemia stem cells and may some day lead to better forms of treatment.

Dans le même numéro de Blood, on parle aussi d'un nouveau médicament contre la leucémie connu sous le nom de TDZD-8

The National Cancer Institute RAID program (Rapid Access to Interventional Development) is funding the fast-track research into DMAPT at the University of Rochester. RAID attempts to push promising new therapeutics into the marketplace more quickly. Additional funding came from the Leukemia and Lymphoma Society and the U.S. Department of Defense. Co-authors and partners include chemists at the University of Kentucky, who contributed to developing the analog form of parthenolide.