Schedule dependence for cisplatin and etoposide multifraction treatments of spheroids

Cisplatin and etoposide are both widely used as antineoplastic chemotherapeutic agents. Two approaches are generally adopted when an attempt is made to maximize the efficiency of these drugs: concurrent use (where synergism is expected) or sequential administrations (exploiting the antiproliferative effects of etoposide). To differentiate between these approaches in a quantitative manner, we exposed an in vitro tumor model (V79 multicell spheroids) to the drugs, using treatment regimens with a constant weekly dose intensity. Some treatment schedules suggested the development of drug resistance, but this resulted from a changing growth fraction in the spheroids rather than from selection for or induction of cellular resistance. Fewer administrations of larger doses were generally less satisfactory than multiple, smaller treatments. The most effective sequence was an alternating regimen, by which the cytoreductive effects of cisplatin resulted in recruitment of quiescent cells into active proliferation, enhancing in turn the efficiency of subsequent etoposide treatment.