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View the Table of Contents for the October 15 issue of Clinical Cancer Research.
Sieuwerts et al. Page 7311
The ADAMs, which stands for a disintegrin and metalloproteinase, comprise a family of membrane proteins. Sieuwerts et al. determined that ADAM-9 and ADAM-11 are able to predict the type of response to tamoxifen treatment in patients with recurrent breast cancer differentially from estrogen receptor (ER) and that the fraction of tumor cells over stromal elements are important in this respect. For tumors with a relatively low percentage of epithelial tumor cells, which comprises a large subgroup of primary breast tumors, ER levels are no longer significantly informative. ADAM-9 and ADAM-11, however, are shown to have potential to predict the effectiveness of tamoxifen therapy for this specific group of tumors.
van der Heijden et al. Page 7508
The Fanconi anemia (FA)/BRCA2 pathway functions in the repair of DNA-interstrand cross-linking agents and is mutated in 5% to 10% of pancreatic carcinomas. van der Heijden et al. tested the sensitivity of FA/BRCA2-mutated pancreatic cancer cell lines— as cells in culture and as xenografts in mice— to a panel of commonly used chemotherapeutic agents. FA/BRCA2-mutated cells were specifically hypersensitive to DNA-interstrand cross-linking drugs in vitro as well as in vivo compared with FA/BRCA2-proficient cells. These results provide pivotal support for a clinical investigation of possible methods to identify patients with a pancreatic carcinoma defect in the FA/BRCA2 pathway and to attempt successful treatment with DNA-interstrand cross-linking agents.
Braess et al. Page 7415
In antineoplastic pharmacotherapy, several highly schedule-dependent agents are used in which dose alone without consideration of the mode of application (bolus, continuous infusion, etc.) is not correlated to treatment effect. Braess et al. have developed a new concept for such agents (e.g. cytarabine, methotrexate) in which the shape of the area-under-the-concentration-time curve (AUC) is quantitatively taken into account by the concentration coefficient N. Via this N-weighted AUC (N-AUC) as a parameter, estimation of treatment effect is now available for cytarabine in acute myeloid therapy that is highly correlated to clinical efficacy.
Sterman et al. Page 7444
Sterman et al. describe the long-term follow-up of 21 patients with malignant mesothelioma who received a single intrapleural “high dose” of a nonreplicative adenoviral vector encoding the herpes simplex virus thymidine kinase “suicide gene” (Ad.HSVtk) in combination with systemic ganciclovir (GCV). Both the E1/E3-deleted vector and the E1/E4-deleted vector were well tolerated and safe, and posttreatment antitumor antibody responses were detected. Several clinical responses were noted, including two long-term (>6.5 years) survivors. The efficacy of Ad.HSVtk/GCV may have been related to induction of antitumor immune responses; approaches aimed at augmenting the immune effects of adenoviral gene transfer (i.e., with the use of cytokines) may engender improved therapeutic responses in otherwise untreatable pleural malignancies.
Bobola et al. Page 7405
Medulloblastomas and primitive neuroectodermal tumors are highly malignant, primary brain tumors in children. To search for urgently needed markers of treatment outcome, Bobola et al. measured apurinic endonuclease, a DNA repair activity. In vitro, suppression of activity in medulloblastoma cells reduced survival following treatment with alkylating agents. In vivo, Cox proportional hazards regression models revealed a strong inverse association of activity in tumor extracts with time to tumor progression after adjuvant radiotherapy plus chemotherapy (HR=1.067, p<0.001); the hazard for progression varied 25-fold in the study population. Thus, apurinic endonuclease activity may confer resistance to combined radiation and chemotherapy and provide a predictive marker of response.