Cytotoxic Effects of Topotecan Combined with Various Active G2/M-Phase Anticancer Drugs in Human Tumor-Derived Cell Lines

Abstract

Topotecan (TPT) is a DNA-Topoisomerase I poison that exhibits antitumor activity. TPT, like other DNA-damaging agents, arrests or delays cell cycle progression during S- and G2-phase in a wide variety of tumor-derived cell lines. Particularly, the G2-arrest gives time for the cell to repair its DNA lesions prior to starting a new cell cycle. Based on these observations, we assessed the interaction between TPT and G2/M-active agents in p53-mutated cell lines of diverse origin in order to achieve cell toxicity. Two short-term sequential schedules were administered (TPT --> G2/M-active drug at the interval of greatest TPT-induced G2/M-phase cell arrest, and G2/M-active drug --> TPT), in three human tumor-derived cell lines with proven sensitivity to the following drugs: Bleomycin in HEp-2 (squamous larynx carcinoma); Docetaxel in SKBr-3 (breast adenocarcinoma); Etoposide in NCI-H23 (non-small-cell lung cancer). Our results show that: 1) Sequential TPT --> G2/M-active drugs are synergistic when administration overlapped the maximum percentage of TPT-induced G2/M-phase cell arrest interval in all three mutated p53 cell lines; 2) the reverse sequential schedule (G2/M-active drug --> TPT) was antagonistic, and being only additive for Etoposide --> TPT association. In conclusion, our findings further support the potential cytotoxic role of TPT in combination with other active drugs when the correct schedule of administration is applied. In addition, they provide a rationale for new applications in clinical trials using short-term sequential TPT --> G2/M-active drugs.

Microwave-assisted synthesis of polypyridyl ruthenium(ii) complexes as potential tumor-targeting inhibitors against the migration and invasion of Hela cells through G2/M phase arrest

“…Furthermore, a large number of studies in the literature [42][43][44][45] have reported that small molecule drugs that induce G2/M phase arrest could eventually induce tumour cell apoptosis. However, aer Hela cells were treated with 4, little apoptosis was observed (Fig.…”

A phase II study of weekly topotecan and docetaxel in heavily treated patients with recurrent uterine and ovarian cancers

“…In vitro data has shown this combination may have synergistic effects on tumor death [43,44]. Docetaxel may have the greatest synergistic effects with topotecan when given at the time of highest topotecan-induced G 2 -phase cell arrest [45]. Both of these drugs are also metabolized by the CYP 3A4 system, possibly potentiating toxicity.…”

Efficacy of Treatment with Irinotecan and Oxaliplatin Combination in FU-Resistant Metastatic Colorectal Cancer Patients

“…The rationale that supports the combination of irinotecan and oxaliplatin is well described in experimental studies [20, 21], moreover the lack of overlapping toxicity profile made it necessary to evaluate this regimen in the clinical practice. Various phase I trials have been recently published using either a weekly, biweekly or 3-weekly administration schedule of irinotecan [16, 17, 18, 19].…”

“…This sequence has a cytokinetic base, since the topoisomerase I inhibitor is phase specific and it can be expected to have an optimal effect on proliferating cells. It has been demonstrated that, when administered before oxaliplatin, irinotecan generates earlier apoptosis and leads to the induction of greater necrotic cell death than that obtained when it is administered after oxaliplatin [20, 21]. Using the sequence of irinotecan followed by oxaliplatin, we intended to favor the more specific action of irinotecan in CRCs with the aim of achieving a possible advantage in terms of tolerability, although we utilized a higher dose compared to other previous studies [16, 19].…”