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Molecular Determinants of Treatment Response in Human Germ Cell Tumors¹

Department of Pathology/Laboratory for Experimental Patho-Oncology, Erasmus Medical Center/Daniel, Josephine Nefkens Institute, 3000 DR Rotterdam, the Netherlands [F. M., H. S., J. W. O., L. H. J. L.]; Department of Pathology, Free University Medical Center, 1081 HV Amsterdam, the Netherlands [G. L. S., R. S.]; and Department of Oncology, Hematology, Immunology, and Rheumatology, University of Tübingen Medical Center, 72076 Tübingen, Germany [F. M., C. B.]

Purpose: Germ cell tumors (GCTs) are highly sensitive to cisplatin-based chemotherapy. This feature is unexplained, as is the intrinsic chemotherapy resistance of mature teratomas and the resistant phenotype of a minority of refractory GCTs. Various cellular pathways may influence the efficacy of chemotherapy. Their impact has not been investigated in a comprehensive study of tumor samples from clinically defined subgroups of GCT patients.

Experimental Design: We investigated proteins involved in regulation of apoptosis (p53, BAX, BCL-2, and BCL-X_L), cell cycle control [p21 and retinoblastoma protein (RB)], and drug export and inactivation [P-glycoprotein, multidrug resistance-associated protein (MRP) 1, MRP2, breast cancer resistance protein, lung resistance protein, metallothionein, and glutathione S-transferase ] immunohistochemically in samples of unselected GCT patients (n = 20), patients with advanced metastatic disease in continuous remission after first-line chemotherapy (n = 12), and chemotherapy-refractory patients (n = 24). Mature teratoma components (n = 10) within tumor samples from all groups were analyzed separately. The apoptotic index was studied by terminal deoxynucleotidyl transferase-mediated nick end labeling assay.

Results: Invasive GCTs of all groups showed a correlation between wild-type p53 and apoptotic index (r_s = 0.66; P < 0.001). The levels of the antiapoptotic proteins BCL-2 and BCL-X_L were generally low. p21 was hardly detectable and did not correlate with p53 (r_s = 0.29; P = 0.07). No significant differences among the three patient groups were identified regarding any of the investigated parameters (all Ps were >0.08), even though only individual samples from chemotherapy-resistant cases showed a strong staining for MRP2 and GST. In contrast to other components, mature teratomas showed an intense p21 and RB staining and were mostly positive for MRP2, lung resistance protein, and GST.

Conclusions: Our results indicate a multifactorial basis for the chemosensitivity of GCTs with lack of transporters for cisplatin, of antiapoptotic BCL-2 family members, of p21 induction by p53, and of RB and an intact apoptotic cascade downstream of p53. These findings suggest a preference for apoptosis over cell cycle arrest after up-regulation of p53. None of the examined parameters offers a general explanation for the chemotherapy-resistant phenotype of refractory tumors. The up-regulation of various factors interfering with chemotherapy efficacy and ability for a p21-induced cell cycle arrest may explain the intrinsic chemotherapy resistance of mature teratomas.

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