Pathobiology of brain metastases.

Brain metastasis is a major cause of systemic cancer morbidity and mortality. Many factors participate in the development and maintenance of brain metastases. The survival of the metastasis depends upon crucial interactions between tumour cells and the brain microenvironment during its development at the new site. This review focuses on the pathobiological mechanisms involved in the establishment and regulation of brain metastases. Developments in molecular biology have vastly expanded our knowledge about the mechanisms of invasion, proliferation, metastatic cell signalling, and angiogenesis in brain metastases. Advances in this understanding of the pathobiology of brain metastasis may lead to novel targeted treatment paradigms and a better prognosis for patients with brain metastatic disease.

Adult-onset hydrocephalus.

Adult-onset hydrocephalus can be acquired from other pathologies, congenital with a late onset, or idiopathic. Subarachnoid hemorrhage, normal-pressure hydrocephalus, tumors, and aqueductal stenosis are the most frequent causes, and clinical presentation may be acute or chronic. The pathophysiology of the more chronic form involves hypoxia and blood vessel changes. The treatment of adult hydrocephalus is dependent on its setting and may involve ventroposterior or ventroanterior shunting or endoscopic procedures.

Therapeutic efficacy of G207 in a novel peripheral nerve sheath tumor model.

Nerve involvement poses a significant obstacle for the management of peripheral nervous system tumors, and nerve injury provides a frequent source of postoperative morbidity. The lack of suitable animal models for peripheral nerve tumors has impeded the development of alternative nerve-sparing therapies. To evaluate the effect of a multimutated replication-competent herpes simplex virus (G207) on the growth of peripheral nerve tumors and on nerve function, we developed a novel peripheral nerve sheath tumor model. Human neuroblastoma-derived cells injected into murine sciatic nerve consistently caused tumor development within the nerve sheath after 2 weeks followed by increasingly severe impairment of nerve function. Tumor treatment by a single intratumoral injection of G207 resulted in significant reduction of functional impairment, inhibition of tumor growth and prolonged survival. Direct injection of G207 viral particles into the healthy nerve sheath caused no obvious neurologic sequelae, whereas injections of wild-type virus resulted in uniform lethality. The results indicate that viral therapy might be considered as a safe alternative to surgical removal of tumors with peripheral nerve involvement.

Corticosteroid administration does not affect viral oncolytic activity, but inhibits antitumor immunity in replication-competent herpes simplex virus tumor therapy.

A multimutated, conditionally replicating herpes simplex virus type 1, G207, has been developed as an effective means of treating human malignant brain tumors. We have shown that intraneoplastic inoculation of G207 induces a specific and systemic antitumor immune response that plays an important role in the antitumor activity, in addition to the direct oncolytic action of G207. Since a large number of malignant brain tumor patients are treated with corticosteroids, it is important to evaluate whether the therapeutic efficacy of G207 is affected by corticosteroid-induced immunosuppression. For a tumor model, we used G207-permissive N18 murine neuroblastoma cells implanted subcutaneously in syngeneic A/J mice. Intraneoplastic inoculation of G207 (10(7) PFU) induced significant suppression of tumor growth whether or not dexamethasone (5 mg/kg) was given. When dexamethasone was given for an extensive time (16 days starting on day -2), all G207-treated mice showed tumor growth despite initial shrinkage, whereas in the saline group, four of eight of the G207-treated mice were cured. Dexamethasone administration significantly reduced serum neutralizing antibodies against G207 at 14 and 21 days after intraneoplastic G207 inoculation. However, there was no difference between the dexamethasone and saline groups in terms of the amount of infectious G207 isolated from tumors. Dexamethasone administration completely abolished G207-induced cytotoxic T lymphocyte activity against N18 cells. These results indicate that the oncolytic activity of G207 is retained under corticosteroid administration. However, intensive immunosuppression may diminish the long-term efficacy of G207 owing to suppression of tumor-specific cytotoxic T lymphocyte induction.

Effect of prior exposure to herpes simplex virus 1 on viral vector-mediated tumor therapy in immunocompetent mice.

Replication-competent, attenuated mutants of herpes simplex virus type 1 (HSV-1) have been shown to be efficacious for tumor therapy. However, these studies did not address the consequences of prior exposure to HSV, as will be the case with many patients likely to receive this therapy. Two strains of mice, A/J and BALB/c, were infected with wild-type HSV-1 by intraperitoneal injection and the immune response was determined by plaque reduction assay for neutralizing antibody and ELISA for IgG and IgM. Syngeneic tumors, N18 neuroblastoma and CT26 colon carcinoma, were implanted subcutaneously in HSV-1 seropositive and naive A/J and BALB/c mice, respectively. Established tumors were subsequently treated intratumorally with a multi-mutated HSV-1, G207. G207 inhibited tumor growth to a similar extent whether the mice were seropositive or not. We next examined the effect of multiple intratumoral inoculations of a 10-fold lower dose of G207 on tumor growth. In the multiple treatment group (biweekly for 3 weeks), 75% of tumors were cured, whereas no cures were seen in the single treatment group. We conclude that HSV seropositivity should not deleteriously affect the efficacy of G207 tumor therapy, and multiple inoculations of virus should be considered for clinical evaluation.

Replication-competent herpes simplex virus vector G207 and cisplatin combination therapy for head and neck squamous cell carcinoma.

Replication-competent virus vectors are attractive therapeutic agents for cancer. G207, a second-generation, multimutated herpes simplex virus type 1 (HSV-1), is one such vector that is safe in primates and efficacious against human tumors in athymic mice. Squamous cell carcinoma is the most frequently encountered malignancy of the head and neck, and the chemotherapeutic agent cisplatin is a standard treatment for recurrent head and neck cancer. In this study we examine the therapeutic potential of G207, alone and in combination with cisplatin, against squamous cell carcinoma. Human squamous cell carcinoma cell lines are sensitive to G207 replication and cytotoxicity in vitro at a multiplicity of infection of 0.01, including cisplatin sensitive (UMSCC-22A), moderately sensitive (UMSCC-38), and weakly sensitive (SQ20B) cell lines. Cisplatin did not inhibit the cytopathic effect of G207. G207 inhibited the growth of established subcutaneous head and neck tumors in athymic mice. The therapeutic effects of cisplatin and G207 in vivo were independent. However, in cisplatin-sensitive tumors (UMSCC-38), combination therapy resulted in 100% cures in contrast to 42% with G207 or 14% with cisplatin alone. We conclude that G207 should be considered for the treatment of head and neck cancer and that combination with chemotherapeutic agents may improve efficacy.

Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide.

Glioblastoma multiforme is the most common form of malignant brain cancer in adults and, unfortunately, is not amenable to treatment with current therapeutic modalities. Human glioblastoma U-87 has many of the distinguishing phenotypic features of primary glioblastoma, including an autocrine form of proliferation, high levels of protein kinase C alpha (PKC alpha), and infiltration via white matter tracts. We show that treatment of mice bearing U-87 xenografts with an antisense phosphorothioate oligodeoxynucleotide (S-oligodeoxynucleotide) against the 3'-untranslated region of PKC alpha mRNA results in suppression of tumor growth. Growth was inhibited in both subcutaneous and intracranial tumors, and in the latter instance, treatment with the antisense PKC alpha S-oligodeoxynucleotide resulted in a doubling in median survival time ( > 80 days), with 40% long term survivors. The antisense S-oligodeoxynucleotide did not produce systemic toxicity in mice with subcutaneous or intracranial tumors after daily intraperitoneal injection for 21 or 80 days, respectively, and a scrambled S-oligodeoxynucleotide with the same nucleotide composition as the antisense S-oligodeoxynucleotide did not produce an antitumor effect. The intratumoral levels of both antisense and scrambled S-oligodeoxynucleotide in subcutaneous tumors were 2 microM after 21 daily doses of 20 mg/kg S-oligodeoxynucleotide. The antisense S-oligodeoxynucleotide selectively reduced the levels of PKC alpha in subcutaneous tumors but not those of protein kinase C epsilon or protein kinase C zeta. This is the first demonstration that the growth of glioblastoma multiforme can be suppressed by an antisense PKC alpha S-oligodeoxynucleotide and suggests that this may represent an effective therapy for this type of malignancy.