METRONOMIC TOPOTECAN CAUSES THERAPY-INDUCED TUMOR CELL SENESCENCE AND LOSS OF AGGRESSIVE PROPERTIES IN MYCN-AMPLIFIED CHILDHOOD CANCER [IN VIVO]

Evidence is accumulating that senescence drives cure in various murine and human malignancies. We demonstrate that metronomic, repetitive low-dose topotecan treatment leads to tumor cell senescence in vitro and in vivo and long-term cure in a model for the aggressive childhood cancer neuroblastoma. By using the senescence-associated secretory phenotype (SASP) as a discriminator for beneficial versus adverse effects of senescence, we identified topotecan as inducer of a favorable SASP. Senescent tumor cells are growth arrested and act growth inhibitory on co-cultured non-senescent tumor cells. MYCN oncogene amplification and expression, hallmarks of aggressive neuroblastoma, are significantly reduced, supporting an initial transition to a more favorable phenotype. These new aspects of metronomic drug treatment are clinically relevant and might apply to other tumor entities. Keywords: stress response, therapy induced senescence, cellular response, cancer treatment, neuroblastoma In total, 6 samples were analysed: The MYCN amplified neuroblastoma cell line STA-NB-10 was subcutaneously transplanted in T-cell deficient nude mice (Crl:CD1/Foxn1nu/nu), tumors were grown until a mean volume of 0.5 cm3 was reached and treated for 2 weeks with 0.1 mg/kg/d Topotecan i.p., daily. After sacrificing the mice, tumors were immediately prepared, snap frozen at liquid N2 and subsequently stored at -80°C.