Showing papers by "Timothy L. Ratliff published in 2003"

Antisense treatment against Ki-67 mRNA inhibits proliferation and tumor growth in vitro and in vivo.

Abstract: The Ki-67 protein is tightly regulated and depends on the proliferative status of a cell. It is present in the nuclei of proliferating cells but absent in resting cells. Since transformation of malignant cells is frequently associated with high cell proliferation and since proliferation is tightly associated with the Ki-67 protein labeling index, this antigen may represent a potential target for cancer therapy. In the present study we determined the ability of a phosphorothioate antisense oligodeoxyribonucleotide (ODN) targeted against Ki-67 mRNA to inhibit tumor cell proliferation specifically in cell culture, in multicellular 3-dimensional spheroids (MCS) and in subcutaneous murine tumor models. Antisense treatment of 1 myeloid and different epithelial tumor cell lines in suspension and monolayer culture, respectively, resulted in specific reduction of Ki-67 mRNA and protein, inhibition of proliferation and increased apoptotic cell death. Multicellular human bladder carcinoma spheroids lost their 3-dimensional structure and underwent cell death after incubation with antisense oligonucleotides. The growth of subcutaneous syngeneic prostatic (p = 0.05) and transitional cell tumors (p = 0.001) in immunocompetent mice was significantly inhibited in antisense-treated animals. From these findings we conclude that antisense inhibition of Ki-67 protein expression may be a rational approach in anticancer therapy. © 2003 Wiley-Liss, Inc.

Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumour activity

Abstract: Intravesical BCG therapy is effective in the treatment of superficial bladder cancer. Both clinical and experimental results suggest a role for cytokines and delayed-type hypersensitivity (DTH) in BCG-induced antitumour immunity. We characterized the modulatory effects of BCG on bladder cytokine expression and determined the relationship between DTH and BCG antitumour activity. The bladders of mice were instilled with BCG through a catheter. Bladder tissue RNA and urine were collected for evaluation of cytokine expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ELISA. IFN-gamma and TNF-alpha, the two major cytokines associated with DTH, were efficiently induced by BCG. IL10, an important down-regulator of DTH, was also induced by BCG. Constitutive levels of IL4 and IL5 were observed, but neither IL4 nor IL5 were modulated by BCG. Similar results were observed in the kinetic analysis of urinary cytokines in patients after intravesical BCG therapy. Production of Th1 (T helper type 1) cytokines (IFN-gamma, IL2 and IL12) preceded that of the Th2 (T helper type 2) cytokine IL10. A tendency toward higher ratios of IFN-gamma versus IL10 for BCG responders also was observed. In animal studies the absence of IL10 abrogated either by antibody inhibition or the use of genetically modified, IL10 deficient (IL10-/-) mice resulted in enhanced DTH responses. Under conditions of enhanced DTH, a significant enhancement in antitumour activity was observed. These data demonstrate that DTH and its associated mononuclear infiltration and cytokine production are important to the antitumour activity of intravesical BCG therapy, and suggest that effects to diminish IL10 production may have therapeutic value.

Chapter 58 – Are Vaccinations for Prostate Cancer Realistic?

Abstract: Tumor cells possess a virtually unlimited number of antigens, the majority of which have not been identified. Vaccination against infectious agents occur prior to exposure in order to prevent disease, whereas the immune system has theoretically already been exposed to the tumor antigens in the case of a cancer vaccine and, therefore, may already be “tolerant” to that antigen. The majority of cancer vaccines focuses on stimulating a different arm of the immune response, cell-mediated immunity, compared to the desired humoral response to infectious agents. The interest in vaccine therapy for cancer has increased tremendously over the past decade. The goal of tumor immunology is to understand the immune response to malignant cells and to be able to use this knowledge to create novel therapeutic strategies. The need for novel and effective adjuvant treatment options for prostate cancer seems obvious. Dramatic advances in available molecular techniques and increasing understanding of antigen presentation and recognition have led to a much renewed interest in the possibility of a cancer vaccine. Tumor escape from the immune surveillance remains largely unexplained, and despite the tremendous interest in identifying antigens for cancer vaccines, few have been found that are truly unique to tumors. The exact role that immunotherapy will have in the management of prostate cancer is yet to be defined and will remain that way for the near future given the time required to complete phase III trials for this disease.