Efficacy of doxorubicin thermosensitive liposomes (40 degrees C) and local hyperthermia on rat rhabdomyosarcoma.

The efficacy of novel thermosensitive liposomes (40 degrees C) containing doxorubicin (Dox-Lip) together with local hyperthermia (HT) was studied on solid growing rat rhabdomyosarcomas. Tumor response and systemic toxicity were evaluated by comparing to free doxorubicin (Free Dox) with or without hyperthermia. Tumors were heated with infrared-A-radiation and drugs were infused intravenously after preheating the tumors followed by a further 60 min of heating at 42.5 degrees C. Recorded temperatures at various locations in the tumors indicated that all intratumoral temperatures, especially at the back rim, were definitely >40 degrees C. After single doses, tumor growth was further inhibited by Dox-Lip+HT compared to Free Dox+HT or Free Dox alone. Repeated treatments with Dox-Lip+HT (2x2.5 mg/kg+HT/2 weeks) resulted in a statistically significant tumor growth delay and was associated with a much lower systemic toxicity. Uptake studies of drugs in blood, tumor and normal tissues showed that Dox-liposomes (40 degrees C) are long circulating liposomes in the blood. However, the enhanced tumor response did not correlate with an increased uptake of Dox-Lip+HT in the tumor. The findings suggest that repeated applications of thermosensitive liposomal doxorubicin (40 degrees C) and local hyperthermia can control primary rat rhabdomyosarcomas while reducing the systemic toxicity of free doxorubicin.

Results of treatment of 112 cases of primary CNS lymphoma.

BACKGROUND: Chemotherapy with or without radiotherapy is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, either as a single agent or in combination with other drugs. Due to the lack of well-conducted randomized trials, the optimal treatment remains controversial. Available retrospective studies are difficult to discuss, however, some common themes can be found. METHODS: One hundred and twelve patients with PCNSL were treated with four different regimens over a period of 24 years. Treatment regimens were: whole-brain irradiation (WBI) alone, MVP (MTX, vincristine, and predonisolone), ProMACE-MOPP hybrid (cyclophosphamide, pirarubicin, etoposide, vincristine, procarbazine, prednisone, and MTX) and R-MTX (rituximab, MTX, pirarubicin, procarbazine, and prednisone) combined-modality therapy. RESULTS: The median failure-free survival was 16 months, and the median overall survival (OS) was 24 months. The 2- and 5-year actuarial probability of survival was 52.4 +/- 4.8% [95% confidence intervals (CI)] and 30.2 +/- 4.8% (95% CI), respectively. The ProMACE-MOPP protocol, Karnofsky performance status (KPS), MTX dose and WBI were associated with good OS by univariate models. By multivariate analysis, MTX dose, WBI dose, and its square dose were significantly associated with good OS. 20-30 Gy WB, and 500 mg/m(2) of MTX dose appeared important determinants of OS. CONCLUSIONS: A modest dose of MTX (500 mg/m(2)) followed by reduced-dose WBI for patients who respond appears a feasible treatment approach that minimizes serious toxicity.

Transcranial imaging of audiogenic epileptic foci in the cortex of DBA/2J mice.

Exposure to intense sound stimuli induces audiogenic seizures in DBA/2J mice. We investigated cortical activities during sound stimulation using flavoprotein fluorescence imaging. Most DBA/2J mice had seizures during intense sound stimulation, with more than half surviving after seizures. Surviving mice were anesthetized with urethane (1.6 g/kg, intraperitoneal), and the skull was exposed and then covered with clear resin. More than 3 days after surgery, the mice were lightly anesthetized with urethane (0.8 g/kg) and cortical activities during intense sound stimulation were visualized. Focal responses appeared near the somatosensory cortex together with spike activities localized in the response area. These findings indicate that epileptic foci of audiogenic seizure are formed in the cortex of DBA/2J mice.

Interstitial hyperthermia with intra-arterial injection of adriamycin for malignant glioma.

A new method for treating malignant glioma by concurrent intra-arterial injection of adriamycin during thermotherapy was performed in seven patients with malignant glioma, four males and three females, with five cases of glioblastoma and two of anaplastic oligodendroglioma. Adriamycin was intra-arterially injected at a dose of 20 mg via the common carotid artery during thermotherapy. The heating procedure was repeated three times combined with chemotherapy in one therapy course, and a total of nine therapy courses were performed in the seven patients. All patients tolerated the protocol well. Based on post-therapy computed tomography, five of the therapy courses achieved partial response, one course resulted in disease progression, and the remaining three courses showed no change. The median time to progression was 3.4 months and the overall median length of survival following stereotactic biopsy was 13.2 months. Facial flushing was observed during eight therapy courses, and extensive alopecia in six therapy courses. Intracystic concentrations of adriamycin were determined in three patients, and marked increases were observed. Intra-arterial injection chemotherapy during hyperthermia is a promising therapeutic method for treatment of malignant glioma with few adverse effects.

Mild hyperthermia plus adenoviral p53 over-expression additively inhibits the viability of human malignant glioma cells.

Adenoviral replacement of the p53 gene has already been proved effective for the treatment of various tumours, including malignant gliomas. However, it is difficult to treat malignant glioma with p53 gene therapy alone because of problems with resistance or a less-than-satisfactory response to the treatment. This study investigated whether heat shock at 43 degrees C (mild hyperthermia) augments the cytotoxic effect of p53 gene transfer on malignant glioma cells expressing wild-type p53 (D54) or mutant p53 (U373-MG and U251-MG). The combination of mild hyperthermia and adenoviral p53 over-expression had an additive inhibitory effect on cellular proliferation in all three cell lines studied. Further, both cell cycle analysis and a DNA fragmentation assay showed that apoptosis was induced by p53 over-expression alone but not by heat shock at 43 degrees C alone. However, p53 over-expression followed by mild hyperthermia additively increased the proportion of cells in which apoptosis was induced, regardless of the endogenous p53 status of the tumour cells. Interestingly, a caspase-independent mechanism was observed to be involved in the p53-induced apoptosis in U251-MG and D54 cells. Taken together, the findings showed that combining adenoviral p53 transfer with mild hyperthermia inhibits the proliferation of malignant glioma cells in an additive manner, irrespective of their endogenous p53 status, suggesting a novel treatment strategy for this malignancy.