Wortmannin, a phosphoinositide 3-kinase inhibitor, selectively enhances cytotoxicity of receptor-directed-toxin chimeras in vitro and in vivo.

BACKGROUND: Generalized resistance of some neoplastic cell lines to treatment with ligand-toxin chimeras has been attributed to an increased rate of lysosomal uptake and degradation following endocytosis of the chimera-receptor complex. Because phosphoinositide 3-kinase (Pl 3-kinase) activity is known to play a role in intracellular trafficking, particularly from endosomes to lysosomes, we hypothesized that co-exposing cells to the Pl 3-kinase inhibitor, wortmannin, might enhance cytotoxicity of ligand-toxin chimeras. METHODS: In vitro, cytotoxicity of five receptor directed-toxin chimeras (bFGF-SAP, bFGF-PE, aFGF-PE, HBEGF-SAP, bFGF-gelonin) and an immunotoxin (11A8-SAP) was examined in the presence or absence of this Pl 3-kinase inhibitor against a panel of human neoplastic cell lines: SK-MEL-5 (melanoma), PA-1 (ovarian teratocarcinoma), DU145 (prostatic carcinoma) and MCF-7 (breast carcinoma). In vivo, antitumor activity of a treatment regimen combining wortmannin (1 or 2 mg/kg i.p.) and bFGF-SAP (10 micrograms/kg i.v.) once a week for 4 weeks was evaluated compared to administration of each agent alone in C3H/HeN mice implanted with the FSallC murine fibrosarcoma. RESULTS: At concentrations greater than the reported Ki for Pl 3-kinase inhibition (1-10 microM), wortmannin enhanced cytotoxicity when combined with saporin or gelonin chimeras, but produced subadditive cytotoxicity when combined with Pseudomonas exotoxin chimeras. When low nanomolar concentrations selective for Pl 3-kinase inhibition (5-100 nM) were examined for effects on one receptor directed-toxin chimera, wortmannin dramatically enhanced bFGF-SAP cytotoxicity in three of the four cell lines. A different Pl 3-kinase inhibitor, LY294002 (Ki approximately 1 microM), however, failed to potentiate bFGF-SAP. When administered to mice, wortmannin combined with bFGF-SAP resulted in a significant decrease in tumor volumes compared to vehicle-treated controls that was not observed in mice treated with either agent alone. CONCLUSIONS: Taken together, these results suggest that although wortmannin increases the cytotoxic efficacy of some receptor-directed chimeras, potentiation may occur through an alternative pathway not involving Pl 3-kinase inhibition.

Susceptibility of Ethiopian bulinid snails to Schistosoma haematobium from Somalia.

Susceptibility of four Ethiopian bulinid snails to a Somalian strain of S. haematobium was tested. Bulinus abyssinicus was highly susceptible and lowland B. africanus was partially susceptible while B. truncatus and B. forskalii were refractory to the parasite. It is suggested that Ethiopian refugees returning from Somalia and/or Somalian refugees entering Ethiopia should be screened and treated for S. haematobium before they are allowed to work/resettle in development areas where B. abyssinicus and B. africanus are known or ecologically suspected to occur.

Colonization of irrigation canals by Bulinus abyssinicus and upsurge of urinary schistosomiasis in the middle Awash Valley of Ethiopia.

The current status of urinary schistosomiasis and snail intermediate 1 hosts in the middle Awash Valley was assessed. Examination of urine by the filtration method for one camp (Assoba) in the Amibara Irrigation scheme showed high human prevalence (70%) and snail infection (7%). Of interest is the fact that now B. abyssinicus, the snail intermediate host of urinary schistosomiasis, has started colonizing the irrigation canals and that our of the infected individuals, 30.3% are itinerant population, possible irrigation workers. The immediate measures to be taken are suggested.