Author Block:
Maria José Guillén, Oscar Cataluña, Mandy Palomares, Raquel López, Práxedes Núñez, Carmen Cuevas, Pablo Avilés. PharmaMar S.A., Madrid, Spain
Abstract Body : Background :
Lurbinectedin (PM01183), a new synthetic tetrahydroisoquinoline alkaloid, is a minor groove specific DNA binder that interacts directly with specific factors involved in DNA repair and transcription pathways. In living cells, PM01183-DNA adducts stall replication and transcription giving rise to double strand breaks, inducing accumulation of cells in the S-phase of the cell cycle and triggering apoptosis. In both the ongoing phase II trials (pancreas and platinum-resistant ovarian cancer) the first stage was concluded with positive results in clinical activity, ensuring the continuity of the trials. Also, phase I trials in combination with doxorubicin and gemcitabine as well as in advanced acute leukemia are ongoing. In vivo studies aimed at defining the synergism of PM01183 combined with taxanes (taxol and docetaxel) are presented here.
Material and Methods :
Athymic mice were implanted with HGC-27 (gastric), A2780 (ovarian), H460 (NSCLC), 22RV1 (prostate) or MDA-MB-231 (breast) cancer cells. Mice bearing tumors (ca. 150 mm3) were allocated (N=6-8/group) to experimental groups, namely: placebo; PM01183 at MTD (0.180 mg/kg [0.54 mg/m2]), 0.75MTD, 0.5MTD and 0.25MTD; taxol (H460, A2780 or HGC-27) or docetaxel (22RV1 or MDA-MB-231) at their MTD, 0.75MTD, 0.5MTD and 0.25MTD; and, PM01183 combined either with taxol or docetaxel at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) MTDs. All treatments were given intravenously once per week during the placebo-treated survival time. The combination index (CI) was determined by the CI-isobol method. When needed, statistical differences for the antitumor effect recorded between groups were determined using two-tailed Mann-Whitney U test.
Results :
In all the experiments, the combination of PM01183 and taxol or docetaxel resulted in more antitumor effect ( P < 0,05 ) than obtained with the more active single agent at the highest dose ( MTD level ) . Analysis of the results by the CI - Isobol method indicated Synergism ( CI < 1,0 ) afther the treatment with PM01183 Plus Taxol of mice bearing HGC - 27 , A2780 , H460 Xenografted tumors . Also , in 22RV1 or MDA- MB231 Tumor bearing animals , the treatment of PM01183 plus Docetaxel resulted in an additive or Synergistic effect .
Conclusion :
An improved (additive or synergism) in vivo antitumor activity was recorded after the treatment with PM01183 plus Taxanes ( Taxol or Docetaxel ) of mice bearing Gastric, Ovarian, NSCLC, Breast or Prostate Xenografted Tumors.
The anti-tumor agent trabectedin has direct effects on tumor cells, blocking cell cycle and proliferation. It also interferes with DNA repair mechanisms and with the activity of selected transcription factors (TF). At the level of the tumor microenvironment trabectedin is cytotoxic to monocytes and Tumor-Associated Macrophages (TAM); inhibits angiogenesis and the production of several inflammatory mediators.
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