The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice.

Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti-leishmanial agent. The compound induces topoisomerase I-mediated DNA-protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topoisomerase of L. donovani and acts as a non-competitive inhibitor interacting with both subunits of the enzyme. Niranthin interacts with DNA-protein binary complexes and thus stabilizes the 'cleavable complex' formation and subsequently inhibits the religation of cleaved strand. The compound inhibits the proliferation of Leishmania amastigotes in infected cultured murine macrophages with limited cytotoxicity to the host cells and is effective against antimony-resistant Leishmania parasites by modulating upregulated P-glycoprotein on host macrophages. Importantly, besides its in vitro efficacy, niranthin treatment leads to a switch from a Th2- to a Th1-type immune response in infected BALB/c mice. The immune response causes production of nitric oxide, which results in almost complete clearance of the liver and splenic parasite burden after intraperitoneal or intramuscular administration of the drug. These findings can be exploited to develop niranthin as a new drug candidate against drug-resistant leishmaniasis.

Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas.

PURPOSE: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma. EXPERIMENTAL DESIGN: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n=24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m(2) for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m(2) for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging. RESULTS: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura. CONCLUSION: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma.

A non-invasive method for detection of intestinal mucositis induced by different classes of chemotherapy drugs in the rat.

BACKGROUND: The Sucrose Breath Test (SBT) is a simple noninvasive technique for the detection of small intestinal mucositis. AIM: We utilised rat models of intestinal mucositis induced by different classes of chemotherapeutic agents to broaden application of the SBT. METHODS: Mucositis was induced in rats by injection of Doxorubicin (Dox), Etoposide (Etop), Irinotecan (Irin), or Cyclophosphamide (Cy) and Etop in combination (Cy+Etop). The SBT was carried out following sucrose gavage, 72 h after chemotherapy. At kill, intestinal tissues were collected for mucositis assessments. RESULTS: SBT for controls was 16.0 +/- 0.6% (mean +/- SEM) cumulative dose at 90 min. Irin, Doxo, Etop, and Cy+Etop significantly decreased the SBT to 53%, 43%, 32% and 30% of saline control values, respectively (p < 0.01) whilst sucrase activity was correspondingly decreased to 60%, 36%, 14% and 2%. There was good concordance with histological mucositis severity in the jejunum, with median scores of 11, 19, 28 and 27. Correlations between SBT, sucrase activity, and histological severity score yielded r(2) values of 0.82. CONCLUSIONS: The SBT detected mucositis induced by the alkylating agent, anthracycline and DNA-topoisomerase inhibitor classes, facilitating the detection of small intestinal dysfunction, providing a further means to screen newly-developed drugs for intestinal side-effects.

Effect of peplomycin or camptothecin-11 on X-ray skin injuries of ICR hairless mice.

In interdisciplinary oncotherapy by radiation and chemical substances, the injurious effects of radiation on the normal skin are occasionally modified by combined chemical substances. In the present experiment, the possible modifying effects of Peplomycin (PEP, 30 mg/kg body weight) and Camptothecin-11, an inhibitor of DNA topoisomerase I (CPT-11, 15 and 50 mg/kg body weight), on radiation skin injury were studied. Macroscopic changes on the thigh skin of male ICR hairless mice (at 8 weeks of age) induced by 10 Gy X-ray irradiation alone and the combined treatment with the anticancer substances were estimated by a modified scoring first reported by Lowy and Baker. Intraperitoneal administration of PEP significantly enhanced radiation skin injury; while CPT-11 (15 mg/kg), within the clinical dose range and in the similar molarities to that of PEP, did not show any appreciable modification effect. Treatment with CPT-11 (50 mg/kg) showed a radiation enhancement without significant difference. The chemotherapeutic radioenhancement ratios of the combined treatments of X-ray and PEP or CPT-11 (15 or 50 mg/kg) were 1.49, 1.17 or 1.34, respectively. Treatment with PEP at the accepted dose showed a radiation enhancement, while CPT-11 did not show any radiation enhancement within the clinical dose.

Effects of CPT-11 (a unique DNA topoisomerase I inhibitor) on a highly malignant xeno-transplanted neuroblastoma.

Although many advances have been made in the management of neuroblastoma, the prognosis of patients with advanced neuroblastoma remains poor, and constant efforts are being made to search for newer effective drugs. CPT-11 is a newly developed derivative of camptothecin and shows a unique anti-tumor activity by inhibiting DNA topoisomerase I. In this study the effects of CPT-11 on a human neuroblastoma xenograft, TNB9, were investigated according to the standard Battelle Columbus Laboratories protocol. TNB9 is one of the most malignant strains of neuroblastoma, showing a homogeneously staining resion (HSR) on chromosome 20 and 80-fold amplification of the N-myc gene. This study disclosed that CPT-11 was highly effective against TNB9. Maximum inhibition rate (IR) was 72.5% at a standard dose and 52.8% even at half the dose. No nude mouse used in this study lost weight after an administration of CPT-11. Plasma pharmacokinetics of CPT-11 administered in this experimental model were compared to that in clinical patients. Our data suggested that CPT-11 might be a promising new drug in the treatment of high-risk neuroblastoma patients and encouraged us to employ CPT-11 in the protocol of the Study Group of Japan.