Epidemiological study of Trichosporon asahii infections over the past 23 years.

Trichosporon is a yeast-like basidiomycete, a conditional pathogenic fungus that is rare in the clinic but often causes fatal infections in immunocompromised individuals. Trichosporon asahii is the most common pathogenic fungus in this genus and the occurrence of infections has dramatically increased in recent years. Here, we report a systematic literature review detailing 140 cases of T. asahii infection reported during the past 23 years. Statistical analysis shows that T. asahii infections were most frequently reported within immunodeficient or immunocompromised patients commonly with blood diseases. Antibiotic use, invasive medical equipment and chemotherapy were the leading risk factors for acquiring infection. In vitro susceptibility, clinical information and prognosis analysis showed that voriconazole is the primary drug of choice in the treatment of T. asahii infection. Combination treatment with voriconazole and amphotericin B did not show superiority over either drug alone. Finally, we found that the types of infections prevalent in China are significantly different from those in other countries. These results provide detailed information and relevant clinical treatment strategies for the diagnosis and treatment of T. asahii infection.

Improved therapeutic efficacy of doxorubicin through conjugation with a novel peptide drug delivery technology (Vectocell).

Improvement in the therapeutic index of doxorubicin, a cytotoxic molecule, has been sought through its chemical conjugation to short (15-23 amino acid) peptide sequences called Vectocell peptides. Vectocell peptides are highly charged drug delivery peptides and display a number of characteristics that make them attractive candidates to minimize many of the limitations observed for a broad range of cytotoxic molecules. The studies reported here characterized the in vitro and in vivo efficacy of a range of Vectocell peptides conjugated to doxorubicin through different linkers. These studies show that the in vivo therapeutic index of doxorubicin can be improved by conjugation with a specific Vectocell peptide (DPV1047) through an ester linker to C14 of doxorubicin, in both colon and breast tumor models. This conjugate was also shown to have significant in vivo antitumoral activity in a model resistant to doxorubicin, suggesting that this conjugate is able to circumvent the multidrug resistance (MDR) phenotype. These experiments therefore provide support for the use of the Vectocell technology with other cytotoxic agents.

CPI-0004Na, a new extracellularly tumor-activated prodrug of doxorubicin: in vivo toxicity, activity, and tissue distribution confirm tumor cell selectivity.

The search for cancer therapies that are more selective for tumor cells and spare normal sensitive cells has been very active for at least 20 years. The extracellularly tumor-activated peptidic prodrug of doxorubicin (Dox) CPI-0004Na (N-succinyl-beta-alanyl-L-leucyl-L-alanyl-L-leucyl-Dox) is potentially such a treatment. Here, we report the results of lethality studies performed with this compound in the mouse, showing that it is up to 4.6 times less toxic than Dox.HCl by the i.v. route and up to 16.2 times after i.p. administration. Pharmacokinetics and tissue distribution data indicate that this reduced toxicity is attributable to a lower uptake of Dox in normal tissues after treatment with CPI-0004Na than after the administration of an equimolar dose of Dox.HCl. For example, heart exposure to Dox is reduced >10-fold. Because of this reduced toxicity, higher doses of CPI-0004Na than of the parent drug could be used to treat nude mice bearing s.c. human breast (MCF-7/6) and colon (LS-174-T and CXF-280/10) tumors. In all three models, the prodrug showed a much improved efficacy as compared with Dox.HCl. Particularly, LS-174-T tumors that do not respond to Dox were inhibited by 68% after treatment with CPI-0004Na. Tissue distribution studies performed with MCF-7/6 tumor-bearing nude mice and comparing CPI-0004Na and Dox.HCl confirmed that the improved activity of the prodrug is actually the result of selective generation and uptake of Dox at the tumor site. Dox levels in tumor tissue were 2-fold higher after treatment with CPI-0004Na than after treatment with an equimolar dose of Dox.HCl, whereas normal tissue levels were reduced 1.4-29-fold.