Activity of the multikinase inhibitor dasatinib against ovarian cancer cells.

BACKGROUND: Here, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer. METHODS: We examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs. RESULTS: Concentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC(50) values (IC(50) range: 0.001-11.3 micromol l(-1)). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73-1.11) or paclitaxel (mean CI values, range: 0.76-1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib. CONCLUSIONS: These data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer.

A field study on malaria prevalence in southeastern Laos by polymerase chain reaction assay.

A detection survey for malaria infection by routine microscopy and polymerase chain reaction (PCR) assay was conducted on 336 inhabitants of two villages in Khammouane Province, Lao People's Democratic Republic (Lao PDR), in July 1997. Malaria infection was demonstrated in 58 (17.3%) subjects by microscopy and in 117 (34.8%) by PCR assay. Specimens positive by both methods were frequent in young villagers, suggesting the presence of many subclinical infections in older persons. The most common species of malaria parasite was Plasmodium falciparum (82.9%). Polymerase chain reaction assay detected mixed infections with 2-4 species in 27 specimens (23.1%). The results demonstrate that there are many subclinical malaria infections with low parasite level and infection with all four human malaria species in Lao PDR.

An epidemiological study on Opisthorchis viverrini infection in Lao villages.

The prevalence of liver fluke, Opisthorchis viverrini, infection in rural and urban communities was studied in Khammouane Province in Lao PDR. The infection was the commonest among the villagers examined, showing the positive rates of 52.9% and 55.0% in two rural communities and 60.7% in an urban community, respectively. The infection rate reached up to 20% or more within 4 years after birth and increased with age to a plateau in the age group over 20 years. The highest prevalence rate was over 80% in the age group of 35-54 years. The age-related patterns of infection in males and females were almost the same, although there were some sex-related differences by village and by age group. Infection with Opisthorchis viverrini appears to be a serious public health problem strongly associated with the frequent eating habit of raw fish in low land Laos.

Plasmodium ovale infections detected by PCR assay in Lao PDR.

Plasmodium ovate infection was demonstrated in 5 out of 143 inhabitants in a village in Lao PDR by blood microscopy and PCR assay. Although the specimen confirmed to be positive for P. ovale by microscopical examination was only one, the target sequences in the 18S rRNA genes of malaria parasite detected in all of the five cases were consisted with those of P. ovale by the PCR assay. This is the first report concerning the presence of so many cases with P. ovale infection in Lao PDR.

An epidemiological survey on intestinal parasite infection in Khammouane Province, Lao PDR, with special reference to Strongyloides infection.

To estimate the current prevalence of intestinal helminth infection in Lao PDR, a parasitological survey was conducted in three villages in Khammouane Province in December 1996, with special reference to Strongyloides infection. A total of 669 fecal samples were collected in the villages and examined by agar-plate culture method and Kato-Katz thick smear method. Intestinal helminths were demonstrated in 82% of the samples as follows: Ascaris lumbricoides (30.5%), Trichuris trichiura (23.7%), hookworm (28.8%), Strongyloides stercoralis (19.0%), Enterobius vermicuralis (3.4%), Opisthorchis viverrini (56.7%) and Taenia sp (3.0%). The infection rates of S. stercoralis were 27.5% and 18.4% in two rural villages, but only 9.4% in an urban village. The highest prevalence rate of Strongyloides infection was obtained in the age group from 20 to 29 years old, although the infection rate already reached 10% in the age group under 10 years old. The prevalence was consistently higher in male subject than females in almost all age groups.

Collection of anopheline mosquitos in three villages endemic for malaria in Khammouane, Lao PDR.

Anopheline mosquito collections were made during the months of May and June (dry season) and August (rainy season), 1996 at villages, Nakham, Namdik and Hinboon Neua in Khammouane Province. Larval collections were also made in 3 slow running streams around Nakham villages in May 1996. Altogether, 3,549 adult females consisting 19 Anopheles species were collected by 3 nights of human and 6 animal bait traps and 3 resting collections. Among them, Anopheles vagus (19.75%), An. philippinensis (15.02%), An. nivipes (11.55%), An. pallidus (11.27%), An. peditaeniatus (8.34%), An. kochi (8.00%) and An. barbirostris (7.27%) were predominant species. The immatures of An. barbirostris, An. minimus, An. maculatus sensu lato, and An. culicifacies were found in the streams of Nakham. It is noteworthy that An. minimus, An. dirus and An. maculatus sensu lato, which are well known malaria vectors in Thailand, were recorded for the first time in this area.