methylcellulose and Brain-Neoplasms

Recent data suggest that inhibition of the Hedgehog pathway could be a therapeutic target for glioblastoma. Alkaloid cyclopamine inhibits Hedgehog signaling, depleting stem-like cancer cells derived from glioblastoma. However, this compound is toxic for somatic stem cells, preventing its use for clinical applications. In this study, we tested a derivatization product of cyclopamine in the form of cyclopamine glucuronide prodrug (CGP-2). This compound was used in vitro and in vivo toward glioblastoma-initiating cells (GIC). Results obtained in vitro indicate that CGP-2 is active only in the presence of β-glucuronidase, an enzyme detected in high levels in necrotic areas of glioblastomas. CGP-2 decreased proliferation and inhibited the self-renewal of all GIC lines tested. Hedgehog pathway blockade by 10 μmol/L of CGP-2 induced a 99% inhibition of clonogenicity on GICs, similar to cyclopamine treatment. Combination of CGP-2 with radiation decreased clonogenic survival in all GIC lines compared with CGP-2 alone. In a subcutaneous glioblastoma xenograft model, a two-week CGP-2 treatment prevented tumor growth with 75% inhibition at 8 weeks, and this inhibition was still significant after 14 weeks. Unlike cyclopamine, CGP-2 had no detectable toxic effects in intestinal crypts. Our study suggests that inhibition of the Hedgehog pathway with CGP-2 is more effective than conventional temozolomide adjuvant, with much lower concentrations, and seems to be an effective therapeutic strategy for targeting GICs.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Design; Drug Screening Assays, Antitumor; Female; Glioblastoma; Glucuronides; Hedgehog Proteins; Humans; Inhibitory Concentration 50; Methylcellulose; Mice; Mice, Nude; Neoplasm Transplantation; Neoplastic Stem Cells; Prodrugs; Veratrum Alkaloids

Polyinosinic-polycytidylic acid, a double-stranded ribonucleic acid that is a potent inducer of interferon production, was used in a stabilized form to treat 11 patients with metastatic renal cell carcinoma. Seven patients completed a full course of 8 infusions at maximum tolerated dosage. All patients experienced transient fever and marked fatigue. Anorexia was mild. Transient leukopenia occurred in 3 patients and reversible elevation in creatinine was observed in 1. All 4 patients with brain metastases became lethargic, and 3 died during or shortly after therapy. Only 2 patients demonstrated measurable total regression of isolated metastases (pleural/pulmonary in 1 and bone in 1) but in both metastases at other sites progressed. No partial regressions were seen. Metastases at all other sites (liver, brain and renal fossa) progressed during therapy. Patients who appeared to respond and who performed best during therapy generally demonstrated a higher performance status initially. Expression of natural cytotoxicity in in vitro testing did not correlate with a demonstrated response to treatment.

Topics: Bone Neoplasms; Brain Neoplasms; Carboxymethylcellulose Sodium; Carcinoma, Renal Cell; Humans; Interferon Inducers; Kidney Neoplasms; Lung Neoplasms; Methylcellulose; Poly I-C; Polylysine

Topics: Adjuvants, Immunologic; Animals; Brain Neoplasms; Carboxymethylcellulose Sodium; Glioma; Interferon Inducers; Methylcellulose; Methylcholanthrene; Mice; Mice, Inbred C57BL; Peptides; Poly I-C; Polylysine; Propionibacterium acnes

Poly(ICLC) preparation, containing poly-L-lysine and poly(I) . poly(C) at a weight ratio of 1:2, was given intravenously at a dose of 0.05 to 0.2 mg/kg to 7 patients with malignant brain tumor. Poly(ICLC) induced significant serum interferon (more than 100 reference units/ml) in all patients. The highest interferon titer induced was 875 reference units/ml. Severe side effect was not observed except fever. Hypotension, leukopenia and elevation of liver enzyme levels were observed as side effects in a few cases.

Topics: Adult; Brain Neoplasms; Carboxymethylcellulose Sodium; Drug Evaluation; Female; Humans; Hypotension; Interferon Inducers; Interferons; Leukopenia; Liver; Male; Methylcellulose; Middle Aged; Molecular Weight; Peptides; Poly I-C; Polylysine

Topics: Animals; Body Weight; Brain Neoplasms; Carboxymethylcellulose Sodium; Dose-Response Relationship, Drug; Interferons; Male; Methylcellulose; Neoplasm Transplantation; Nimustine; Nitrosourea Compounds; Peptides; Picibanil; Poly I-C; Polylysine; Rats

Interferon inducing activity, antitumor activity and toxicity of poly ICLC (poly IC stabilized with poly L-Lysine and carboxymethyl cellulose) in rodents were studied. SD strain rats were injected intravenously with poly IC or poly ICLC. Interferon in rat plasma was assayed by a plaque reduction method using stomatitis virus. The peak level of plasma interferon of the poly ICLC injection rat was as high as that of poly IC injection rat, and in the former, high level of plasma interferon persisted for 4-12 hours. Next, brain tumor-bearing rats were treated intravenously with poly ICLC and observed for death daily. Weekly treatment with 1 mg/kg of poly ICLC increased the mean survival time although no antitumor effect was observed with poly IC. The LD 50 value of poly IC was 33.5 mg/kg, and that of poly ICLC was 18.6 mg/kg and as to poly ICLC administration, no remarkable side effect was recognized below the dose of 1.5 mg/kg. In clinical trials, poly ICLC was given intravenously at the dose of 0.05-0.2 mg/kg to 9 patients with malignant brain tumor. (6 patients were glioblastoma, 1 was astrocytoma, and 2 were ependymoma.) In 2 patients, poly ICLC was administered once, in 2 patients twice, in 2 patients 3 times, and in 3 patients more than 5 times. The interval of each administration was 7 days. Poly ICLC induced high level of serum interferon (more than 100 reference unit/ml) in all patients and over 100 unit/ml of interferon was maintained for 24 hours. The highest interferon titer induced was 875 unit/ml. The most frequently encountered toxic reaction was fever, which occurred in all cases. The mean peak temperature elevation was 1.9 degrees C, which usually occurred 4-8 hours after drug administration. Modest hypotention was detected in one case. Leucopenia was detected in 3 cases. These abnormalities were all modest, and improved in a few days. As to the effect of poly ICLC, neurological improvement was recognized in 3 cases, and in one of them, remission on CT scan was also recognized.

Topics: Adult; Animals; Astrocytoma; Brain Neoplasms; Carboxymethylcellulose Sodium; Ependymoma; Female; Glioma; Humans; Infusions, Parenteral; Interferon Inducers; Male; Methylcellulose; Mice; Middle Aged; Neoplasms, Experimental; Peptides; Poly I-C; Polylysine; Rats