Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound.

BACKGROUND: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU) can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes selectively to brain tumors. METHODS: Firefly luciferase (Fluc)-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice. RESULTS: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug ratio (P < 0.001). Combining repeated pulsed HIFU with AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin has similar antitumor effects. CONCLUSION: This study demonstrates that targeted or untargeted liposomal doxorubicin, followed by repeated pulsed HIFU, is a promising high-dose chemotherapy method that allows the desired brain tumor region to be targeted specifically.

Enhanced expression of alpha 2,6-sialyltransferase ST6Gal I in cervical squamous cell carcinoma.

OBJECTIVE: Increased messenger ribonucleic acid (mRNA) expression of beta-galactoside alpha 2,6-sialyltransferase I (ST6Gal I) is important in squamous cell carcinoma (SCC) of the cervix. In many tissues, ST6Gal I is transcriptionally regulated through the use of promoters that originate in the mRNA species that diverge in the 5'-untranslated regions. To clarify the roles of ST6Gal I mRNA species in cervical SCC, we investigated their expression, including a "constitutive" promoter (placental or Y + Z form), "hepatic" promoter (H form), and a specific lymphoblastic promoter (X form), in normal and SCC tissues of the cervix using real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR). METHODS: Expression of the ST6Gal I species was investigated in normal cervical tissue samples (n = 38) and FIGO IB1 cervical SCC samples (n = 38) by relatively quantitative real-time RT-PCR, using primers designed for amplification of a portion of the coding region common to all mRNA species or ones for amplification of the placental transcript, the hepatic transcript, or lymphoblastic transcript. RESULTS: ST6Gal I mRNA expression was significantly increased in cancerous tissues compared to that in normal tissues (P = 0.004, Mann-Whitney U test; P < 0.001, paired t test). Expression of the Y + Z form did not appear to be affected by cancer transformation, since it was detected at comparable levels in normal and cancerous tissues (P = 0.986), but H form expression was significantly enhanced in cancerous tissues compared to that in normal tissues (P < 0.001, Mann-Whitney U test and paired t test). Surprisingly, the X form could be detected in some patients with and without cancer, but the detection rate was significantly higher in patients with cancer (86.8% vs 52.6%, respectively; P = 0.021, Fisher's exact test). Although the X transcript was detected at a low level compared to the H and Y + Z transcripts, its expression was also significantly enhanced in patients with cancers compared to those without cancers (P < 0.001, Mann-Whitney U test and paired t test). CONCLUSIONS: An increased level of hepatic transcripts may be important in cancer transformation because the transcripts contribute to enhance ST6Gal I expression in cancerous tissues.

Expression of sialyltransferase family members in cervix squamous cell carcinoma correlates with lymph node metastasis.

OBJECTIVE: Altered messenger ribonucleic acid (mRNA) expression of the four sialyltransferases (STs including ST3Gal I, ST3Gal III, ST3Gal IV, and ST6Gal I) is important in squamous cell carcinoma of the cervix. This study further investigates their changes in mRNA expression of the four STs in FIGO stage IB1 squamous cell carcinoma to assess the extent of sialylation associated with lymph node metastases. METHODS: Alterations in ST mRNA expression in FIGO IB1 cervical squamous cell carcinomas (n = 79) were examined by semiquantitative reverse transcription-polymerase chain reaction. RESULTS: Both ST6Gal I mRNA and ST3Gal III mRNA expressions were significantly increased in patients with lymph node metastases compared to those without lymph node metastases (P = 0.002 and P = 0.001, respectively, Mann-Whitney U test). Using receiver operating characteristic curves of ST ratio index for accuracy comparison of lymph node metastases, ST3Gal III and ST6Gal I were observed to be fairly interchangeable (area under the curve (AUC) of 3Gal I = 0.810; AUC of 6Gal I = 0.786, significance of difference between AUC = 0.810). High ST6Gal I expression was associated with other invasive properties of cervical cancer, such as deep stromal invasion and presence of lymph-vascular space involvement. ST6Gal I expression seemed to be more enhanced in bigger tumors. CONCLUSIONS: Our results suggested that ST3Gal III and ST6Gal I were of importance for the lymph node metastases in FIGO IB1 cervical cancer patients; more specifically, overexpression of ST6Gal I was of crucial relevance for the presence of poor prognostic factors, such as deep stromal invasion and lymph-vascular space involvement and lymph node metastases.