Host distribution and response to antitumor alkylating agents of EMT-6 tumor cells from subcutaneous tumor implants

1997 ◽  
Vol 40 (1) ◽  
pp. 87-93 ◽  
Author(s):  
Sylvia A. Holden ◽  
Yasunori Emi ◽  
Yoshihiro Kakeji ◽  
David Northey ◽  
B. A. Teicher
Keyword(s):  
Tumor Cells ◽  
Alkylating Agents ◽  
Subcutaneous Tumor ◽  
Host Distribution ◽  
Antitumor Alkylating Agents

Postlabeling detection of DNA adducts of antitumor alkylating agents

1996 ◽  
Vol 38 (1) ◽  
pp. 71-80 ◽  
Author(s):  
Guo-Hao Zhou ◽  
B. A. Teicher ◽  
Emil Frei III.
Keyword(s):  
Dna Adducts ◽  
Alkylating Agents ◽  
Antitumor Alkylating Agents

Monoclonal antibody 2C5-mediated binding of liposomes to brain tumor cells in vitro and in subcutaneous tumor model in vivo

2005 ◽  
Vol 13 (6) ◽  
pp. 337-343 ◽  
Author(s):  
Bhawna Gupta ◽  
Tatiana S. Levchenko ◽  
Dmitry A. Mongayt ◽  
Vladimir P. Torchilin
Keyword(s):  
Monoclonal Antibody ◽  
Brain Tumor ◽  
Tumor Cells ◽  
Tumor Model ◽  
Subcutaneous Tumor ◽  
Brain Tumor Cells

Effect of hemoglobin solution on the response of intracranial and subcutaneous 9L tumors to antitumor alkylating agents

1993 ◽  
Vol 33 (1) ◽  
pp. 57-62 ◽  
Author(s):  
Beverly A. Teicher ◽  
Sylvia A. Holden ◽  
Krishna Menon ◽  
Robert E. Hopkins ◽  
Maria S. Gawryl
Keyword(s):  
Alkylating Agents ◽  
Hemoglobin Solution ◽  
Antitumor Alkylating Agents

SDX-105 (Treanda™), Active in Non-Hodgkin’s Lymphoma Cells, Induces the Mitotic Catastrophe Death Pathway.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4593-4593 ◽  
Author(s):  
Lorenzo M. Leoni ◽  
Christina Niemeyer ◽  
Heather Bendall ◽  
Jack Reifert ◽  
Brandi Bailey
Keyword(s):  
Tumor Cells ◽  
Mechanism Of Action ◽  
Chromatin Condensation ◽  
Alkylating Agents ◽  
Mitotic Catastrophe ◽  
Cross Resistance ◽  
Pcr Analysis ◽  
Dna Damaging Agents ◽  
Anti Tumor Activity ◽  
In Cells

Abstract SDX-105 (Treanda™) is an alkylating agent with a distinct mechanism of action that has been shown to be active in clinical trials in NHL and CLL patients refractory to traditional DNA-damaging agents. SDX-105 induces unique changes in gene expression in NHL cells and displays a lack of cross resistance with other 2-chloroethylamine alkylating agents. Quantitative PCR analysis confirmed that the G2/M checkpoint regulators Polo-like kinase 1 (PLK-1) and Aurora A kinase (AurkA) are down-regulated in the NHL cell line SU-DHL-1 after 8 hours of exposure to clinically relevant concentrations of SDX-105. No changes in these same genes were observed when cells were exposed to equi-toxic doses of chlorambucil or an active metabolite of cyclophosphamide. Because our previous studies demonstrated that SDX-105 treatment can activate apoptotic cell death pathways, we examined the ability of SDX-105 to induce cytotoxicity in cells unable to undergo ‘classical’ caspase-mediated apoptosis. Multi-drug resistant MCF-7/ADR cells and p53 deficient RKO-E6 colon adenocarcinoma cells were exposed for two or three days to either 50 μM SDX-105 alone or 50 μM SDX-105 and 20 μM pan-caspase inhibitor zVAD-fmk. Although zVAD-fmk was able to inhibit SDX-105 induced increases in Annexin-V-positive cells, microscopic analysis of nuclear morphology using the DNA stain DAPI in cells treated with either SDX-105 alone or in combination with zVAD-fmk showed increased incidence of micronucleation. Multi/micro-nucleation and abnormal chromatin condensation are both hallmarks of mitotic catastrophe and have been observed in tumor cells exposed to microtubule-binding drugs such as the vinca alkaloids and taxanes. Activation of mitotic catastrophe may amplify the cytotoxicity of SDX-105 and its activity in tumor cells where classical apoptotic pathways are inhibited. This may explain, at least in part, the potent anti-tumor activity of SDX-105 in tumor cells refractory to conventional 2-chloroethylamine DNA-damaging agents. Additional studies are ongoing to further elaborate the role of mitotic catastrophe in SDX-105’s mechanism of action. The capacity to induce mitotic catastrophe may explain the anti-tumor activity of SDX-105 in chemotherapy relapsed and resistant patients.

Long-Term Exposure to Pomalidomide-Dexamethasone in Pts with Refractory Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3466-3466
Author(s):  
Brigitte Pegourie ◽  
Marie Odile Petillon ◽  
Lionel Karlin ◽  
Denis Caillot ◽  
Murielle Roussel ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Prolonged Exposure ◽  
Safety Management ◽  
Alkylating Agents ◽  
Dose Intensity ◽  
Median Number ◽  
Duration Of Treatment ◽  
Multicentre Phase ◽  
Combining Data ◽  
One Year

Abstract Background. The IFM2009-02 study was launched in 2009, and randomized 84 patients (pts) with pomalidomide (oral 4 mg daily) and dexamethasone (oral 40 mg weekly) given either 21 days out of 28 or continuous. Whilst the overall median PFS was 4.6 months - this end stage very advanced RRMM population, we observed that 40% of the patients had a prolonged PFS and subsequently OS in the trial. We sought to analyze the characteristics of 58 pts that had more than 3 months of pomalidomide to study the effect of long exposure to Pomalidomide. Method. IFM 2009-02 was a multicentre phase 2 study of pts with RRMM who had at best a stable disease with the last course of bortezomib and of lenalidomide, or who were refractory to bortezomib and lenalidomide (IMWG). This analysis was performed on the ITT population combining data from the 2 study arms. We have analyzed the characteristics of pts according to duration of treatment with pomalidomide and dexamethasone 3 months to one year (<1 year) or more than one year (≥1 year). Results. 60% and 40% of pts were exposed to pomalidomide for <1 year and ≥1 year, respectively. The ORR for the <1 year group was 43%, the median PFS 4.6 months (CI95% 4;6) with only 6% at 12 months, and the median OS 15 months (4;6) and 65% at 12 months, 40% at 18 months. For the ≥1 year group, the response rate and survival were strikingly different, ORR at 83%, PFS 20.7 months, OS not reached (CI95% 40;-) and 100% at 12 months, 91% at 18 months. Of the pts in the <1 year, 87% have died versus 35% in the ≥1 year group. Of note, death of most pts occurred during the follow up period post pomalidomide therapy , however in a far greater extent for the <1 year group, 96% versus 67%, that could suggest it was more difficult to salvage these pts post pomalidomide. We next sought to identify the characteristics of the 2 groups. Interestingly, the median number of prior lines was similar across groups, 5 (range 1-10), with 89% and 79% of the pts exposed to more than 3 lines and 17% and 22% exposed to more than 6 lines, for the <1 year and ≥1 year groups, respectively. 40% and 48% of pts had Bortezomib as last line, 29% and 43% Lenalidomide, 43% and 26% and alkylating agent. Similarly, 80% and 74% of pts were refractory to Bortezomib, 89% versus 87% to Lenalidomide, 65% versus 75% to alkylating agents, 74% and 87% to the last line of therapy, respectively. 74% and 70% were double refractory (Bortezomib and Lenalidomide) and 60% and 70% were triple refractory (double +last line), respectively. The time from diagnosis to IFM 2009-02 study entry was also similar between cohorts, 5.8 and 6.5 years for <1 year and ≥1 year groups; however with 6% versus 26% of pts, entering the study in less than 3 years since diagnosis. There was no difference in terms of patients characteristics between groups, either patients-based such as gender, age, weight, or myeloma-based characteristics. However, serum beta 2m level was higher at diagnosis in the <1 year compared to the ≥1 year, 54% versus 35%, with a slightly more adverse cytogenetic profile 35% versus 12%, with the limitation that this was not available for all the patients. Presence of plasmacytoma/EMD was also greater in the former group, 20% versus 4%, respectively. It seems that the <1 year had more intrinsic adverse features of the tumor cells compared to the ≥1 year group. There was no clear difference in terms of safety management of pomalidomide and/or dexamethasone, with respect to the daily dose intensity of Pomalidomide (median, 3.0 and 2.9 mg/day), and the relative dose intensity of pomalidomide that was 89% and 84%, respectively; similar to the rate of dose reduction and dose interruption. Conclusion. Pomalidomide and dexamethasone is effective and well tolerated in these heavily pre-treated MM pts refractory to Bortezomib and Lenalidomide, with approximately 40% of the patients having a prolonged exposure to treatment, which translated into a significantly prolonged OS. Our study suggests that patients with more intrinsic adverse features of Myeloma tumor cells could not have prolonged exposure to pomalidomide as they progressed within a year from start of pomalidomide. Future studies should examine optimizing pomalidomide therapy in those patients, such as using multidrug pomalidomide-based combined regimens to prolong exposure to pomalidomide and improve the survival of these patients. Disclosures Karlin: Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Stoppa:Celgene Jansen: Honoraria.

A new concentrated perfluorochemical emulsion and carbogen breathing as an adjuvant to treatment with antitumor alkylating agents

1992 ◽  
Vol 118 (7) ◽  
pp. 509-514 ◽  
Author(s):  
Beverly A. Teicher ◽  
Sylvia A. Holden ◽  
Gulshan Ara ◽  
Chul Soo Ha ◽  
Terence S. Herman ◽  
...  
Keyword(s):  
Alkylating Agents ◽  
Perfluorochemical Emulsion ◽  
Antitumor Alkylating Agents
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