Comparison of in vitro activity of epipodophyllotoxins with other chemotherapeutic agents in human medulloblastomas

Abstract

Surgical specimens from 15 medulloblastoma patients were used to establish early passage cultures. In vitro sensitivity to a battery of cytotoxic agents, including some in current medulloblastoma treatment protocols, was measured. Drug sensitivity was assessed at clinically relevant drug concentrations using the 3H-thymidine uptake method. Tumours were predicted to be sensitive if greater than 37% were killed by exposure to drugs at clinically achievable levels. A poor response to vincristine (Vcr), cis-platin (CDDP), hydroxyurea (HU) or diaziquone (AZQ) (no responders), and cytosine arabinoside (AraC) (1/12), was seen. Nine of ten tumours tested were sensitive to mafosfamide (Mfs); seven out of 12 were sensitive to carmustine (BCNU), 12 of 13 to teniposide (VM-26) and seven of 13 to etoposide (VP16-213). VM-26 was the best of the agents tested with most tumours responding to very low concentrations of drug, suggesting that the role of epipodophyllotoxins in treatment of brain tumours be further investigated. Despite the marked sensitivity of the medulloblastomas to the epipodophyllotoxins, three early passage cultures were much more resistant to these drugs than the average for the group. The basis of this resistance was investigated. Deficient cellular uptake of drug was excluded as a cause of resistance. One resistant early passage culture displayed low cellular activity of topoisomerase II and decreased levels of drug induced enzyme-DNA strand break activity. This was not the case for the other resistant early passage cultures: the basis of resistance in these cells does not appear to be due to any previously reported mechanism.