Treatment of neoplastic meningitis with intrathecal 9-nitro-camptothecin.

The topoisomerase I inhibitor, 9-nitro-camptothecin (9NC), is highly tumoricidal against glioblastoma multiforme (GBM) in vitro. However, systemic administration of 9NC has not shown the expected efficacy in clinical trials. This failure may be due to the rapid hydrolysis of 9NC in plasma from the active form to the inactive and myelosuppressive form in the presence of human albumin at physiologic pH. Concurrent treatment with anticonvulsants and dexamethasone, drugs indispensable for the supportive therapy of patients with GBM, has also been shown to decrease plasma concentrations of these drugs. Intrathecal drug delivery circumvents the blood-brain barrier and minimizes systemic toxicity. Intrathecal delivery of 9NC may also have the more specific advantage of significantly reducing the hydrolysis of 9NC that occurs after systemic delivery due to the more favorable pH and reduced albumin content in cerebrospinal fluid. The present study evaluated the toxicity and efficacy of intrathecal delivery of 9NC in an athymic rat model of neoplastic meningitis. Toxicity tests showed that 0.3 micromol (5000 microM), 0.03 micromol (500 microM), 0.003 micromol (50 microM), or 0.0003 micromol (5 microM) of 9NC administered intrathecally to the athymic rats caused no evidence of clinical or histological toxicity. Intrathecal administration of 0.3 micromol (5000 microM) of 9NC twice a week for three doses to athymic rats with neoplastic meningitis induced by the GBM cell line, U87MGDeltaEGFR, resulted in a 26% increase of median survival compared to the control group (p < 0.005). These results suggest that intrathecal treatment with 9NC may be useful for patients with GBM neoplastic meningitis.

Targeted therapy for glioblastoma multiforme neoplastic meningitis with intrathecal delivery of an oncolytic recombinant poliovirus.

PURPOSE: The toxicity and antitumor activity of regional intrathecal delivery of an oncolytic recombinant poliovirus, PVS-RIPO, was evaluated in rodent models of glioblastoma multiforme neoplastic meningitis. EXPERIMENTAL DESIGN: To evaluate for toxicity, PVS-RIPO was administered into the spinal cord of transgenic mice that express the human poliovirus receptor, CD155, and into the intrathecal space of athymic rats without tumor. To evaluate efficacy, two different doses of PVS-RIPO were administered intrathecally 3 days after athymic rats were inoculated intrathecally with an aggressive human glioblastoma multiforme xenograft. RESULTS: No clinical or histologic evidence of toxicity was found. In efficacy studies, median survival was increased by 174.47% from 8.5 days in the group treated with UV light-inactivated virus to 15 days in the rats treated with 1.0 x 10(7) plaque-forming units (pfu) of PVS-RIPO (P < 0.0001). A similar increase in median survival was seen in the group receiving 1.0 x 10(9) pfu PVS-RIPO (P < 0.0001); however, there was no statistically significant dose-response relationship (P = 0.345). In addition, 1 of 10 rats in lower-dose PVS-RIPO-treated group and 3 of 10 rats in higher-dose PVS-RIPO-treated group survived >60 days after tumor cell inoculation and had no evidence of residual tumor at autopsy. CONCLUSION: These results suggest that intrathecal treatment with PVS-RIPO may be useful for treatment of neoplastic meningitis in patients with glioblastoma multiforme and provides a rationale for clinical trials in this area.

Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus.

PURPOSE: Spread to the central nervous system (CNS) and the leptomeninges is a frequent complication of systemic cancers that is associated with serious morbidity and high mortality. We have evaluated a novel therapeutic approach against CNS complications of breast cancer based on the human neuropathogen poliovirus (PV). EXPERIMENTAL DESIGN: Susceptibility to PV infection and ensuing rapid cell lysis is mediated by the cellular receptor of PV, CD155. We evaluated CD155 expression in several human breast tumor tissue specimens and cultured breast cancer cell lines. In addition, we tested an oncolytic PV recombinant for efficacy in xenotransplantation models of neoplastic meningitis and cerebral metastasis secondary to breast cancer. RESULTS: We observed that breast cancer tissues and cell lines derived thereof express CD155 at levels mediating exquisite sensitivity toward PV-induced oncolysis in the latter. An association with the immunoglobulin superfamily molecule CD155 renders breast cancer a likely target for oncolytic PV recombinants. This assumption was confirmed in xenotransplantation models for neoplastic meningitis or solitary cerebral metastasis, where local virus treatment dramatically improved survival. CONCLUSIONS: Our findings suggest oncolytic PV recombinants as a viable treatment option for CNS complications of breast cancer.

Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa).

Iressa (ZD1839) is a p.o.-active, selective, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks signal transduction pathways implicated in cancer cell proliferation, survival, and host-dependent processes promoting cancer growth. EGFR is up-regulated in primary malignant tumors of the central nervous system (CNS) and in many systemic tumors that metastasize to the CNS. The purpose of our study was to evaluate the efficacy and toxicity of p.o.-administered ZD1839 for the treatment of established intracerebral (i.c.) tumors expressing EGFR or the tumorigenic mutated variant EGFRvIII, which is constitutively phosphorylated. Oral administration of ZD1839 at 50 or 100 mg/kg/day for 3 weeks in athymic mice with established i.c. A431 human epidermoid carcinoma expressing EGFR increased median survival by 88% (P = 0.009) and 105% (P < 0.001), respectively. Additionally, there was no evidence of systemic or CNS toxicity. However, ZD1839 failed to inhibit either s.c. or i.c. in vivo tumor growth when tumorigenicity was conferred by EGFRvIII. Western blotting revealed that treatment with ZD1839 virtually ablated phosphorylation of EGFR Tyr-1173 in A431 tumors. However, treatment of NR6M tumors with ZD1839 only partially decreased phosphorylation of EGFRvIII Tyr-1173 while up-regulating overall expression, suggesting that EGFRvIII may not be susceptible to the same molecular mechanisms of tyrosine kinase inhibition as EGFR. In conclusion, ZD1839 is active in a brain tumor model expressing EGFR, but not EGFRvIII, as EGFR mutations may lead to relative therapeutic resistance. On the basis of these observations, we believe that clinical trials of ZD1839 against brain tumors expressing EGFR are warranted, but that special consideration should be given to tumors that coexpress EGFRvIII.