Cisplatin

Injectable biodegradable polymer poly(sebacic-co-ricinoleic acid), P(SA-RA) is currently under development for intratumoral (IT) delivery of drugs for treating solid tumors. This study presents formulation development, pharmacokinetic and efficacy studies of two anticancer drugs (cisplatin and paclitaxel) formulated with P(SA-RA) polymer. In pharmacokinetic study, systemic exposure and pharmacokinetic parameters of cisplatin/paclitaxel following single intravenous (IV) or subcutaneous (SC) doses of cisplatin/paclitaxel was compared with intramuscular (IM) or SC doses of cisplatin/paclitaxel formulated with P(SA-RA) polymer in male CD rat. Simultaneously, the tumor reduction effect and toxicity for these formulations were evaluated in human FaDu head and neck tumor xenograft subcutaneous nude mouse model.

P õ 0.001). With regard to recurrences, a significant decrease in with free surgical margins due to the responses obtained pelvic failures in the neoadjuvant chemotherapy group was ob-[10-14]. Our group previously published reports on the use served (P õ 0.001). Survival was improved in bulky resectable of neoadjuvant chemotherapy for cervical cancer [10, 15, cases (N Å 81% vs C Å 69%, P õ 0.05). Pathological findings for 16]. This update-the final report from our clinical trialthe surgical specimens revealed differences between both groups because all the risk factors such as parametrial and lymph node describes additional patients and longer follow-up. metastases, tumor bulk, and vascular embolism had been de-MATERIALS AND METHODS creased (P õ 0.001). Conclusion: Neoadjuvant chemotherapy can improve survival Selection of Patients, Study Design, and Evaluation because of increased operability with free survival margins and a Methods decrease in pathologic risk factors in unselected, bulky (ú4 cm A prospective randomized study of the management of diameter) stage Ib patients. ᭧ 1997 Academic Press patients with squamous carcinoma of the cervix uteri, stage 61

Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors and, importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABRA5, which encodes the α5-subunit of the GABAA receptor complex, in aggressive MYC-driven, "Group 3" medulloblastomas. We hypothesized that modulation of α5-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABRA5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABRA5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOXA5 target gene expression. siRNA-mediated knockdown of HOXA5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABRA5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOXA5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor.

The interactions between the two boxes A and B of HMG 1 and 1 Centre de Biophysique cis-diamminedichloroplatinum(II)-modified DNA containing a single Moleculaire, CNRS intrastrand cross-link at the d(GpG) site were studied by DNase I Rue Charles Sadron footprinting and circular dichroism. The DNAase I cleavage patterns of the 45071 Orleans Cedex 2 France HMG box-platinated DNA complexes are identical, the two boxes inhibiting the DNase I cutting over at least 15 and 12 nucleotide residues in the 2 DIBIT, San Raffaele platinated strand and the complementary strand, respectively. As judged by Scientific Institute, via circular dichroism, the two boxes have the same a-helical content (56%) and Olgettina 58, I-20132 Milano they induce the same conformational changes in the platinated DNA. Italy