Most anticancer drugs fail to impact patient survival since they fail to cross the blood-
brain tumor barrier (BTB) at therapeutic levels. For example,
Temozolomide (TMZ) exhibits some antitumor activity against
brain tumors, so does
Trastuzumab (
Herceptin, Her-2 inhibitor), which might be effective against Her2 neu overexpressing
gliomas. Nevertheless, intact BTB and active efflux system may prevent their entry to
brain tumors. Previously we have shown that
potassium channel agonists increased
carboplatin and Her-2 neu antibody delivery in animal
glioma models. Here, we studied whether
potassium channel agonist increase TMZ and
Herceptin delivery across the BTB to elicit antitumor activity and increase survival in nude mice with human glial
tumor. The K(Ca) channel activity and expression was also evaluated in human
glioma tissues. We administered
NS-1619,
calcium-dependent
potassium (K(Ca)) channel agonist, with [(14)C]-TMZ, and quantified TMZ delivery. The results clearly demonstrate that when given systemically both TMZ and
Herceptin do not cross the BTB in significant amounts, however,
NS-1619 co-infusion with [(14)C]-TMZ and
Herceptin resulted in enhanced
drug delivery to
brain-tumor cells. The combination treatment of TMZ and
Herceptin also showed improved antitumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with
brain tumor, when co-infused with K(Ca) channel agonists. In conclusion, K(Ca) channel agonists may benefit
brain tumor patients by increasing anti-neoplastic agent's delivery to
brain tumors. A clinical outcome of this research is the discovery of a novel drug delivery system that circumvents the BBB/BTB to benefit
brain tumor patients.