PM01183 Synergizes With Topoisomerase I Inhibitors In Vitro And In Vivo .

AACR ,  April 2013 .
Author Block:

 Carlos Galmarini, Maria José Guillen, Victoria Moneo, Luis Francisco Garcia, Mandy Palomares, Oscar Cataluña, Carmen Cuevas, Pablo Avilés. PharmaMar S.A., Madrid, Spain .

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. The in vitro and in vivo synergism of PM01183+ topoisomerase I inhibitors is presented here.

Material and Methods:

 In vitro:

 PM01183+topotecan synergism was tested in a panel of 12 tumor cell lines. In vivo: Athymic mice were implanted with SW1990 (pancreas), HT29 (colon) or H460 (NSCLC) cancer cells. Mice bearing HT29 or H460 tumors (ca. 150 mm3) were allocated to 13 groups (N=6-8/group): placebo; PM01183 at MTD (0.180 mg/kg [0.54 mg/m2]), 0.75MTD, 0.5MTD and 0.25MTD; irinotecan at MTD (50 mg/kg [150 mg/m2]), 0.75MTD, 0.5MTD and 0.25MTD; and, PM01183+irinotecan at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) MTDs. Animals bearing SW1990 tumors received treatments (single or combination) at the MTD levels. Treatments were given intravenously once per week (PM01183) or every 4 days (irinotecan) during the placebo-treated survival time. The combination index (CI) was determined by the CI-isobol method.

Results
The combination of PM01183 plus topotecan in NSCLC (A549), melanoma (SK-MEL-2), hepatocarcinoma (HepG2), colon (HT29), pancreas (PANC-1) and glioma (U87MG) cells was considered synergistic. In vivo, a synergistic antitumor effect  ( CI < 1.0 ) was seen after the treatment with PM01183 + Irinotecan in the HT 29 ( CI = 0,93 ) and H 460 ( CI = 0,30 ) experimental models . Also , in SW 1990 tumor bearing animals , the treatment with the combination of PM01183 and Irinotecan  produced more Antitumor effect ( P < 0,05 ) than the more active single in this experiment ( Irinotecan at MTD level ) .
Conclusion:

PM01183 synergizes the in vitro effect of topotecan in several tumor cell lines including NSCLC, melanoma, hepatocarcinoma, colon, pancreas and glioma. In agreement with the in vitro results, the treatment of mice xenografted with colon, NSCLC or pancreas tumors with PM01183 combined with a topoisomerase I inhibitor (irinotecan) resulted in synergistic antitumor activity.

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