Small cell carcinoma of the prostate: an underrecognized entity.

Adenocarcinoma is by far the most commonly diagnosed histologic subtype among prostate malignancies. Historically, there has been little awareness of the rare but lethal small cell carcinoma (SCC) in association with prostate cancer. Within the last decade, however, several reports have documented the existence of a neuroendocrine-like tumor arising from cells in the prostate. There is evidence that the development of poorly-differentiated neuroendocrine cells (similar to those found in oat cell carcinomas of the lung) can be seen in the progression of an initially pure adenocarcinoma, possibly due to the totipotential nature of the basal or reserve cells normally present in the prostatic acini. Although pure SCC is rare, admixtures of adenocarcinoma and small cell components may be more prevalent than previously believed. Since effective treatment of a prostatic tumor, or part of a tumor, with an SCC etiology differs from that of pure adenocarcinoma, early recognition of any histologic or clinical changes in the patient with prostate cancer may alter the course of the disease.

Combination gene therapy with adenoviral vector-mediated HSV-tk+GCV and IL-12 in an orthotopic mouse model for prostate cancer.

We previously demonstrated significant therapeutic activities associated with adenoviral vector-mediated Herpes Simplex Virus/thymidine kinase (AdHSV-tk) with ganciclovir (GCV) in situ gene therapy in the RM-1 orthotopic mouse prostate cancer model and interleukin-12 (AdmIL-12) in situ gene therapy in the RM-9 orthotopic mouse prostate model for prostate cancer. In both protocols, local cytotoxicity and activities against pre-established lung metastases were demonstrated. To test whether combined AdHSV-tk+GCV+IL-12 gene therapy would lead to enhanced therapeutic effects when compared to either treatment alone, we used RM-9 mouse prostate cancer cells in both orthotopic and pre-established lung metastases models of prostate cancer. Combined treatment with a single injection of optimal doses of AdHSV-tk+GCV or AdmIL-12 led to significantly increased suppression of orthotopic tumor growth. IL-12 gene therapy alone was more effective than AdHSV-tk+GCV in suppressing spontaneous lymph node metastases and pre-established lung metastases but combination gene therapy did not result in additional anti-metastatic activities. Combination gene therapy also did not achieve significantly better animal survival compared to AdHSV-tk+GCV or AdmIL-12 alone. Analysis of localized antitumor activities demonstrated that AdHSV-tk+GCV therapy induced higher levels of necrosis compared to AdmIL-12 or combination therapy. However, both treatments alone and combination therapy produced similar increases in apoptotic index. To address the possible mechanisms of locally co-operative cytotoxic activities, we analyzed the systemic natural killer (NK) response and the numbers of tumor-infiltrating immune cells using quantitative immunohistochemical analysis. AdHSV-tk+GCV therapy alone led to detectable increases in iNOS-positive cells, CD4+and CD8+T-cells and moderately increased numbers of F4/80 (macrophage selective)-positive cells within treated tumors. In contrast, AdmIL-12 elicited a highly robust pattern of tumor infiltration for all four of these immune cells that was in general mimicked by combination therapy. Further analysis of the accumulation of transforming growth factor-beta1 (TGF-beta1) immunohistochemical staining demonstrated that AdHSV-tk+GCV treatment, but not AdmIL-12 treatment, produced cancer cell-associated increases in this cytokine relative to control Ad-beta-gal injections. Interestingly, local injection with AdHSV-tk+GCV induced significant splenocyte-derived NK cell cytolytic activities with maximal response 7 days following treatment, whereas AdmIL-12 injection produced significantly higher NK activity with maximal response 2 days following injection. The combined treatment produced a higher systemic NK response over the 14-day treatment period. Depletion of NK cells in vivo demonstrated that this immunocyte subpopulation was responsible for early locally cytotoxic activities induced by AdHSV-tk+GCV but not AdmIL-12 and that NK activities were largely responsible for activities against pre-established metastases generated by both gene therapy protocols. Prostate Cancer and Prostatic Diseases (2001) 4, 44-55

Prostate cancer gene therapy: comparison of adenovirus-mediated expression of interleukin 12 with interleukin 12 plus B7-1 for in situ gene therapy and gene-modified, cell-based vaccines.

We have documented previously that adenovirus-mediated interleukin 12 (IL-12) gene therapy is effective for orthotopic tumor control and suppression of pre-established metastases in a preclinical prostate cancer model (Y. Nasu et al., Gene Ther., 6: 338-349, 1999). In this report, we directly compare the effectiveness of an adenovirus that expresses both IL-12 and the costimulatory molecule B7-1 (AdmIL12/B7) with one that expresses IL-12 alone (AdmIL-12) using the poorly immunogenic RM-9 orthotopic murine model of prostate cancer. We document AdmIL-12/B7-mediated secretion of IL-12 and increased surface expression of B7-1 in infected RM-9 tumor cells. A significant reduction in orthotopic tumor size and increased survival was demonstrated in mice treated with a single orthotopic injection of AdmIL-12/B7 compared with AdmIL-12 or controls. Six of 19 animals treated with AdmIL-12/B7 survived long term with apparent eradication of the primary tumor in contrast to one of 38 animals in the AdmIL-12-treated group. Orthotopic treatment of tumors with both vectors led to an infiltration of both CD4+ and CD8+ immunoreactive cells, with AdmIL-12/B7 treatment having a more prolonged infiltration of CD8+ cells. AdmIL-12/B7 was also more effective than AdmIL-12 or controls at suppression of pre-established metastases. We further developed a vaccine model based on s.c. injection of infected, irradiated RM-9 cells and found that both AdmIL-12 and AdmIL-12/B7 are effective at suppressing the development and growth of challenge orthotopic tumors using this protocol.

Adenovirus-mediated interleukin-12 gene therapy for prostate cancer: suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model.

Interleukin-12 (IL-12) can elicit potent antitumoral effects that involve the recruitment of specific immune effector cells. We investigated the efficacy of a single injection of a recombinant adenovirus expressing murine IL-12 (AdmIL-12) directly into orthotopic mouse prostate carcinomas generated from a poorly immunogenic cell line (RM-9) derived from the mouse prostate reconstitution system. Significant growth suppression (> 50% reduction of tumor weight) and increased mean survival time (23.4 to 28.9 days) were observed compared with controls. Suppression of pre-established lung metastases was also observed following the injection of AdmIL-12 into the orthotopic tumor. Cytolytic natural killer cell activity was markedly enhanced 1-2 days after virus injection. Immunohistochemical analysis showed significantly elevated intratumoral infiltration of CD4+ and CD8+ T cells 7 days after virus injection. However, splenocyte-derived cytotoxic T lymphocytes were not detected during the 14 days following treatment. Increased numbers of nitric oxide synthase-positive macrophages were seen in the AdmIL-12 treated group 7 days following injection. Systemic inhibition of natural killer cells with antiasialo-GM1 serum led to increased numbers of lung metastases in AdmIL-12-treated orthotopic tumors but did not affect local tumor growth. In this model system the antitumor effects of a single injection of adenovirus-mediated IL-12 appears to be based to a large extent on the activation of nitric oxide synthase in macrophages and possibly T cell activities, whereas the relatively early cytolytic activity of natural killer cells are largely but not exclusively responsible for the antimetastatic effects.

Superconductivity at 40 K in the Oxygen-Defect Perovskites La2-xSrxCuO4-y.

Structural, magnetic, and electronic properties of compounds in the series La2-xSrx CuO4-y for 0.05

Superconductivity and antiferromagnetism in boron-rich lattices.

Ferromagnetism, antiferromagnetism, or superconductivity has been discovered in most hexa- and dodecaborides.