Sequential X-irradiation induced acquired resistance to oxaliplatin but increased sensitivity to cisplatin in two human teratoma cell lines in vitro.

UNLABELLED: Cisplatin (CDDP) and oxaliplatin (OXA-P) are potential therapeutic drugs in the treatment of testicular cancer. However, the emergence of drug resistance has been documented not only in patients after chemotherapy but also subsequently to fractionated X-irradiation. Specific radiation-induced biochemical alterations may play a role in the observed resistance. Since irradiation influences the cellular responses to chemotherapy, this study investigated changes in the expression of key proteins in the regulation of DNA repair and apoptosis subsequent to sequential irradiation. MATERIALS AND METHODS: Logarithmically growing human teratocarcinoma cell lines 2101 EP and H 12.1 were irradiated (10 fractions of 4 Gy in vitro) to establish the sub-lines 2101 EP/DXR-10 and H 12.1/DXR-10. Radiosensitivity was assayed using a clonogenic survival assay. Drug response was assayed using a sulforhodamine B assay. Expression of p53, PARP, hMSH2 and Fas was detected by Western blotting. RESULTS: Both DXR-10 sub-lines showed a significant increase in sensitivity towards CDDP as compared to their parental cell line, however, there was a concomitant increase in resistance against OXA-P. No significant changes in radiosensitivity between parental and DXR-10 cell lines were observed. In addition, there was an up-regulation of PARP, p53, hMSH2 and Fas in the DXR-10 sub-lines, implicating induced damage tolerance and repair mechanisms following irradiation. CONCLUSION: These results suggest that radiation preceding chemotherapy might induce resistance to subsequent chemotherapy with oxaliplatin but not to cisplatin. This is a novel observation and, if confirmed, particularly in other tumor types, may have clinical implications.

[Sinonasal teratocarcinosarcoma: a clinical, radiologic and pathologic study of 5 cases].

OBJECTIVE: To study the clinical, radiologic and pathologic features, as well as differential diagnosis of teratocarcinosarcoma in nasal cavity and paranasal sinuses. METHODS: Light microscopic examination and immunohistochemical study was performed in 5 cases of sinonasal teratocarcinosarcoma. The clinical, radiologic and pathologic features were analyzed and the literature was reviewed. RESULTS: All 5 patients were males and their age ranged from 34 to 43 years (mean age = 39 years). The clinical presentation was nasal obstruction, epistaxis and headache. Physical examination often revealed a polypoid mass with contact bleeding. Computed tomography showed a homogeneous nasal mass with obturation of sinuses. Cystic changes, calcification or ossification was not observed. Histologically, the tumor showed a heterogeneous admixture of components from the 3 germ cell layers, exhibiting various degrees of maturation. Squamous epithelium, smooth muscle cells, chondro-osseous tissue, intestinal or respiratory type epithelium, "fetal-type" clear cells and immature neuroepithelium were commonly seen. Immunohistochemical study demonstrated that the epithelial component expressed cytokeratin and epithelial membrane antigen, while the mesenchymal component variably expressed vimentin, smooth muscle actin and S-100 protein. On the other hand, the neuroepithelial component expressed neuron-specific enolase, synaptophysin and chromogranin, and the primitive component expressed CD99. The initial biopsy diagnosis included capillary hemangioma, olfactory neuroblastoma, craniopharyngioma and malignant mixed tumor. Follow-up information was available in all patients. Two of which had local recurrence and 1 had cervical lymph node metastasis. CONCLUSIONS: Sinonasal teratocarcinosarcoma is a rare and highly malignant tumor occurring in sinonasal tract. It manifests mainly in adult males and is characterized by a complex admixture of teratomatous and carcinosarcomatous components. "Fetal-type" clear cells, squamous epithelium and immature neuroepithelium represent important histologic characteristics useful in diagnosis.

Control of radiosensitivity of F9 mouse teratocarcinoma cells by regulation of histone H2AX gene expression using a tetracycline turn-off system.

The mouse histone H2AX has unique COOH-terminal serine residues that are phosphorylated in response to double-strand DNA breaks introduced by ionizing radiation. This suggests that H2AX acts to maintain genomic stability. We constructed a tetracycline (tet)-directed turn-off vector and integrated it into F9 mouse teratocarcinoma cells by homologous recombination. In homozygously recombined cells, expression of the histone H2AX gene was repressed to 0.02% of the expression observed in wild-type cells by the addition of doxycycline, an analog of tet. Sensitivity of cells with repressed H2AX expression to X-irradiation was increased 1.95x, indicating that DNA repair was impaired by repression of H2AX. When we s.c. injected tet-regulated F9 cells into the flanks of mice, tumor growth was slightly suppressed by X-irradiation in H2AX-repressed tumors, whereas without X-irradiation, tumor growth did not differ by H2AX status. Thus, H2AX might be a potential molecular target for sensitizing cancer cells to radiotherapy to minimize required irradiation doses.

Sinonasal teratocarcinosarcoma.

Sinonasal teratocarcinosarcoma (SNTCS) is a distinctly rare tumor characterized by a variegated histologic architecture of epithelial and mesenchymal components. By reported accounts, SNTCS is a highly malignant tumor displaying rapid, aggressive growth. Prognosis is poor: less than 45% of all patients survive past 5 years. Combination surgery and radiotherapy currently appear to be the most effective treatment. This report presents a 76-year-old African American man with a SNTCS in the right nasal cavity and paranasal sinuses. The patient was treated with combination surgical excision and postoperative radiation therapy. The clinical and pathologic features and clinical course will be discussed.

Teratocarcinosarcoma of the nasal cavity. Report of a case showing favorable prognosis.

We report a very rare case of teratocarcinosarcoma of the nasal cavity showing a favorable prognosis. The patient was a 66-year-old man with a mass completely obstructing the right nasal cavity. Subsequently, extirpation of the mass and Denker-Watsuji operation were performed, and the patient was treated with a combination of radiation therapy and chemotherapy. Neither recurrence nor distant metastasis was observed during follow-up lasting 30 months. Histologic examination of the resected mass revealed several tissue elements including columnar and squamous epithelia with atypia, smooth muscle cells with rare mitotic activity, and neuroectodermal tissue. The glandular epithelium and smooth muscle cells were reminiscent of a primitive intestinal organoid structure, suggestive of teratomatous tumorigenesis. Our case and a review of the literature indicate that the absence of invasiveness to the stroma or surrounding tissue is closely related to a favorable prognosis.

Acquired coronary artery-pulmonary artery connection.

We report a patient who underwent resection of a mediastinal tumor with postoperative irradiation. Cardiac catheterization fifteen years later demonstrated coronary artery-pulmonary artery fistulas from both the right and left coronary arteries. This case report raises the issue of whether external beam irradiation may have been integral in neovascularization and the development of this acquired abnormality.

External beam radiation therapy as an agent in the aetiology of carcinoma of the bile duct: a report on two patients.

Two cases of biliary duct carcinoma occurring in patients who had received prophylactic abdominal irradiation 17 years previously are described. Although external beam radiation has been implicated in the aetiology of many malignancies, there is only one previous report of it being associated with carcinoma of the bile duct. All patients receiving external beam irradiation for curable malignancies require long term follow-up so that treatment induced malignancies may be detected.

Radiation-induced apoptosis in F9 teratocarcinoma cells.

We have found that F9 murine teratocarcinoma cells undergo morphological changes and internucleosomal DNA fragmentation characteristic of apoptosis after exposure to ionizing radiation. We studied the time course, radiation dose-response, and the effects of protein and RNA synthesis inhibitors on this process. The response is dose dependent in the range 2-12 Gy. Internucleosomal DNA fragmentation can be detected as early as 6 h postirradiation and is maximal by 48 h. Cycloheximide, a protein synthesis inhibitor, and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, an RNA synthesis inhibitor, both induced internucleosomal DNA fragmentation in the unirradiated cells and enhanced radiation-induced DNA fragmentation. F9 cells can be induced to differentiate into cells resembling endoderm with retinoic acid. After irradiation, differentiated F9 cells exhibit less DNA fragmentation than stem cells. This indicates that ionizing radiation can induce apoptosis in non-lymphoid tumours. We suggest that embryonic tumour cells may be particularly susceptible to agents that induce apoptosis.