Nikola Banishki

The objective of this study was to determine whether the so-called "shift" or "drift" problem might occur when generic anti-epileptic drugs are interchanged, and thus to assess if generic anti-epileptic drugs are interchangeable and can be used in an efficacious and safe way on the basis of their bioequivalence to one and the same reference product. The bioequivalence of topiramate and gabapentin generics was evaluated. For proper interstudy comparison, individual exposure data (AUC and C(max)) for each bioequivalence study present in the registration dossier was normalized based on the absolute exposure data of one of two innovators. The exposure-normalized plasma concentration curves of the generic product arms between studies were compared, providing indirect evidence of bioequivalence of the different generics. Additionally, comparisons were made for generic-generic as well as innovator-innovator exchange based on absolute exposure data from individual bioequivalence studies. In almost all cases, estimated 90% confidence intervals of the AUC and C(max) ratios for generic-generic interchange were within the routine 80-125% criterion. When absolute, non-corrected exposure data were used for this interstudy comparison, in a number of cases 90% confidence intervals outside the 80-125% criterion were found upon interchanging generics from two studies. However, a similar pattern of 90% confidence intervals outside the 80-125% criterion was observed for the comparison of innovator arms, despite the fact that the innovator was identical in all studies. Our results strongly indicate that the so-called drifting problem upon generic-generic substitution does not result in important differences in exposure upon exchanging topiramate generics or gabapentin generics.

P-glycoprotein (P-gp) is the most studied ATP-binding cassette transporter, known to be able to cause multidrug resistance. The relevance of P-gp for clinical drug resistance remains controversial, however. Using our K14cre;Brca1F/F;p53F/F conditional mouse model of hereditary breast cancer, we previously found that modestly elevated expression levels of the mouse P-gp genes Mdr1a (Abcb1a) and/ or Mdr1b (Abcb1b) are sufficient to cause resistance to the topoisomerase II (TOP2) inhibitor doxorubicin. To study P-gp-independent resistance mechanisms, we bred our model onto a P-gp-deficient background. When transplanted into P-gp-proficient mice, these tumors were hypersensitive to the maximum tolerable doxorubicin dose and usually did not acquire drug resistance. Only when we lowered the dose to 50%, resistance eventually occurred. Tumors that were resistant to the 50% dose showed a stable resistance phenotype upon transplantation into new recipient animals and subsequently also acquir...

Many breast cancers respond to chemotherapy or hormonal therapy, however, the lack of tumor eradication is a central clinical problem preceding the development of drug resistant tumors. We have previously studied responses of mammary tumors generated in the K14cre;Brca1F5-13/F5-13;p53F2-10/F2-10 mouse model for hereditary breast cancer to clinically relevant anti-cancer drugs such as doxorubicin, topotecan, cisplatin and the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (1-4). The BRCA1- and p53-deficient tumors generated in this model are hypersensitive to these drugs and never become resistant to cisplatin due to the large, irreversible deletion in Brca1 (5). We show here that even dose-dense treatment with a maximum tolerable dose of cisplatin does not result in tumor eradication. This is not due to the trivial possibility that the drug-resistant remnants are poorly accessible to drug, since we found a homogeneous distribution of the platinum-DNA adducts throughout the tumor. To explain this result we have addressed the hypothesis that the lack of eradication of drug-sensitive tumors is due to increased in vivo chemotherapy resistance of tumor-initiating cells (TICs). Using the CD24 and CD49f cell surface markers which detect normal mouse mammary stem cells, we have identified TICs in BRCA1- and p53-deficient tumors. In addition to the Lin-/CD24+/CD49f+ subpopulation, we show that a larger population of Lin-/CD24+/CD49f-cells also has tumor-initiating capability in at least two serial orthotopic transplantations, suggesting that these are not more differentiated transit-amplifying cells. However, we did not find an enrichment of TICs in cisplatin-treated tumor remnants. We conclude that in this model the resistance of cisplatin-surviving cells cannot be attributed to special biochemical defense mechanisms of TICs. Instead we will present data supporting the hypothesis that surviving TICs arrest in their cell cycle and ‘hibernate’ until the drug is gone. Using Brca1−/−;p53−/− cell lines derived from the mouse tumors we found that only Brca1−/−;p53−/− cells that were in the G0/G1 phase of the cell cycle 24h after cisplatin treatment were capable of forming new colonies, whereas cells in G2 or M were not. Hence, a p53-independent arrest in G0/G1 appears to underlie the lack of eradication of residual Brca1−/−;p53−/− cells. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A14

We describe a simple device for the aseptic collection of environmental water samples at high spatial resolution to depths of 50m. To demonstrate the utility of this technique we present geochemical and archaeal community data from samples collected throughout the water column of a stratified lake.