1.
FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer.
Moore, KN, Vergote, I, Oaknin, A, Colombo, N, Banerjee, S, Oza, A, Pautier, P, Malek, K, Birrer, MJ
Future oncology (London, England). 2018;(17):1669-1678
Abstract
Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response.
2.
[Ex-vivo-chemoresponse testing of head and neck cancer: an old hat?].
Wichmann, G, Körner, C, Dietz, A
Laryngo- rhino- otologie. 2011;(8):464-8
Abstract
Reliable prediction of the chance of a successful treatment of head and neck squamous cell carcinoma by cytostatics and targeting therapies would be very valuable, since HNSCC due to their heterogenic biology mostly respond non-uniformly and moreover with low response rates. To raise the prospect of chemotherapy by using multimodal therapies usually goes hand in hand with a higher incidence of severe adverse events and acute toxicity but also chemo-associated increased cancer risk following successful treatment. In addition, the increasing numbers of treatment options without availability of reliable prognostic biomarkers for a probably successful outcome make the decision for one or the other medication to something rather like gambling. Therefore, quite early a pre-therapeutic predictive exvivo chemoresponse testing of bioptic specimens was intended. However, the results gained mostly were disillusioning and allowed not for reliable prediction of chance of successful outcome of treatment with tolerable doses of the pharmaceuticals and in particular their combinations. Predictive testing, hence, was belittled as improper for the clinical context. Based on advanced methods, some working groups reassume this subject. This review describes recent advances in ex-vivo chemoresponse testing, discusses pre-requisites which have to be fulfilled before their inclusion into decision-making, and outlines why ex-vivo chemoresponse testing probably is not an old hat.
3.
Implications of increased tissue transglutaminase (TG2) expression in drug-resistant breast cancer (MCF-7) cells.
Herman, JF, Mangala, LS, Mehta, K
Oncogene. 2006;(21):3049-58
Abstract
The development of resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of breast cancer. Ways to block or overcome this resistance are objects of intense research. We have previously shown that cancer cells selected for resistance against chemotherapeutic drugs or isolated from metastatic tumor sites have high levels of a calcium-dependent protein crosslinking enzyme, tissue transglutaminase (TG2) but no direct link between TG2 and resistance was established. As TG2 can associate with the beta members of the integrin family of proteins, we hypothesized that TG2 promotes cell survival signaling pathways by activating integrins on the surface of these cells. To test this hypothesis, we studied the expression of TG2 and its interaction with various integrins in drug-resistant MCF-7 breast cancer cells. TG2 closely associated with beta1 and beta5 integrins on the surface of drug-resistant MCF-7 (MCF-7/Dox and MCF-7/RT) cells. The incubation of TG2-expressing drug-resistant MCF-7 cells on fibronectin (Fn)-coated surfaces strongly activated focal adhesion kinase, an event that leads to the activation of several downstream signaling pathways and, in turn, can confer apoptosis-resistant phenotype to cancer cells. The role of TG2 in Fn-mediated cell attachment, cell growth, and cell survival functions was further analysed by small interfering RNA (siRNA) approach. Inhibition of TG2 by siRNA-inhibited Fn-mediated cell attachment and cell survival functions in drug-resistant MCF-7 cells. We conclude that the expression of TG2 in breast cancer cells contributes to the development of the drug-resistance phenotype by promoting interaction between integrins and Fn.
4.
Modulation of P-glycoprotein-mediated multidrug resistance in K562 leukemic cells by indole-3-carbinol.
Arora, A, Seth, K, Kalra, N, Shukla, Y
Toxicology and applied pharmacology. 2005;(3):237-43
Abstract
Resistance to chemotherapeutic drugs is one of the major problems in the treatment of cancer. P-glycoprotein (P-gp) encoded by the mdr gene is a highly conserved protein, acts as a multidrug transporter, and has a major role in multiple drug resistance (MDR). Targeting of P-gp by naturally occurring compounds is an effective strategy to overcome MDR. Indole-3-carbinol (I3C), a glucosinolates present in cruciferous vegetables, is a promising chemopreventive agent as it is reported to possess antimutagenic, antitumorigenic, and antiestrogenic properties in experimental studies. In the present investigation, the potential of I3C to modulate P-gp expression was evaluated in vinblastine (VBL)-resistant K562 human leukemic cells. The resistant K562 cells (K562/R10) were found to be cross-resistant to vincristine (VCR), doxorubicin (DXR), and other antineoplastic agents. I3C at a nontoxic dose (10 x 10(-3) M) enhanced the cytotoxic effects of VBL time dependently in VBL-resistant human leukemia (K562/R10) cells but had no effect on parent-sensitive cells (K562/S). The Western blot analysis of K 562/R 10 cells showed that I3C downregulates the induced levels of P-gp in resistant cells near to normal levels. The quantitation of immunocytochemically stained K562/R10 cells showed 24%, 48%, and 80% decrease in the levels of P-gp by I3C for 24, 48, and 72 h of incubation. The above features thus indicate that I3C could be used as a novel modulator of P-gp-mediated multidrug resistance in vitro and may be effective as a dietary adjuvant in the treatment of MDR cancers.
5.
[The multidrug tumor cell resistance phenotype caused by the impaired cell death program].
Blokhin, DIu
Vestnik Rossiiskoi akademii meditsinskikh nauk. 2004;(12):16-20
Abstract
The paper shows the role of tumor cell apoptosis induction in the mechanism of cancer cytoreductive therapy and the significance of the impaired cell death program for the pathogenesis of the phenotype of multidrug and radiation resistance resulted from the use of specific antitumor therapy and from the natural course of tumor progression.