Promotion of tumor progression induced by continuous low-dose administration of antineoplastic agent gemcitabine or gemcitabine combined with cisplatin

Abstract

Major finding: This study observes a previously neglected pharmacological phenomenon and investigates its mechanism of that the continuous low-dose administration of some antineoplastic agents in certain dose ranges can promote tumorigenesis and tumor progression in vitro and in vivo, through stimulation of tumor cell functions directly as well as enhancement of tumor angiogenesis by BMDCs recruitment indirectly. The results alert to a potential risk in current empirically based continuous low-dose chemotherapy regimens such as metronomic chemotherapy.

Background and objectives: There are indications that certain antineoplastic agents at low dosages may exhibit abnormal pharmacological actions, such as promoting tumor growth. However, the phenomenon still needs to be further confirmed, and its underlying mechanisms have not yet been fully elucidated.

Methods: Gemcitabine (GEM) and cisplatin (CDDP) were employed as representative antineoplastic agents to observe effects of continuous low-dose chemotherapy with GEM or GEM combined with CDDP (GEM+CDDP) on tumor formation and growthin xenograft tumor models in vivo. Tumor and endothelial cell functions, apoptosis, cell cycle analysis, as well as bone marrow derived cells (BMDCs) mobilization, were evaluated with transwell, MTT or flow cytometry analysis in vitro, respectively. Histological methods were employed to assess angiogenesis in tumor tissues.

Results: The results showed that tumor formation and growth were both significantly promoted by GEM or GEM+CDDP at as low as half of the metronomic dosages, which were accompanied by enhancements of angiogenesis in tumor tissues and the release of proangiogenic BMDCs in the circulating blood. Additionally, GEM or GEM+CDDP at low concentrations dramatically facilitated the proliferation, migration, and invasion of tumor cells in vitro. Cell-cycle arrest, activation of associated apoptotic proteins, and inhibition of apoptosis were also observed in tumor cells.

Conclusions: These findings indicate that, the continuous low-dose administration of GEM and GEM+CDDP can promote tumorigenesis and tumor progression in vivo by inhibiting apoptosis, mobilizing BMDCs, and promoting angiogenesis in certain dose ranges. These findings urge further investigations to avoid the potential risks in current empiric continuous low-dose chemotherapy regimens with antineoplastic agents.

Keywords: Angiogenesis; Antineoplastic agents; Bone marrow derived cell; Low-dosage chemotherapy; Metronomic chemotherapy.