Experimental infection of inbred mouse strains with Candida albicans provides a good model system to identify host genetic determinants that regulate onset of, response to, and ultimate outcome of disseminated candidiasis. The A/J mouse strain is exquisitely sensitive to infection with C. albicans, while the C57BL/6J strain is relatively resistant, as measured by survival following intravenous injection of Candida blastospores. This differential susceptibility is caused by an A/J-specific loss-of-function mutation in the C5 component of the complement pathway. C5 plays several critical roles in host response to infection, including target lysis and phagocyte recruitment. Therefore, to determine which of its functions were required for host resistance to candidiasis, a detailed comparative analysis of pathophysiology and host response to acute C. albicans infection was conducted in A/J and C57BL/6J mice. C5-sufficient C57BL/6J mice were found to succumb late in infection due to severe kidney pathology, typified by fungal replication and robust neutrophil-based inflammatory response associated with extensive tissue damage. In contrast, A/J mice were moribund within 24 h postinfection but displayed little if any kidney damage despite an inability to mobilize granulocytes and a high fungal load in the kidney. Rather, C5 deficiency in A/J mice was associated with higher levels of circulating cytokines tumor necrosis factor alpha, interleukin-6, monocyte chemotactic protein 1 (MCP-1), MCP-5, and eotaxin in response to C. albicans. Transfer of the C5-defective allele from A/J onto a C57BL/6J genetic background in recombinant congenic strain BcA17 recapitulated the phenotypic aspects of the susceptibility of A/J mice to C. albicans, confirming the causative role of C5 deficiency in the dysregulated cytokine response.

Urokinase-type plasminogen activator (uPA) is a serine protease associated with tissue remodeling, cellular invasiveness, matrix degradation and tumor growth. Over-expression of uPA by the rat prostate-cancer cell line Dunning R3227, Mat LyLu, results in increased tumor metastasis to several non-skeletal and skeletal sites. Histological examination of these skeletal lesions has shown them to be primarily osteoblastic. In the present study we examined the capacity of a selective inhibitor of uPA enzymatic activity, 4-iodo benzo[b]thiophene-2-carboxamidine (B-428), to prevent the development of tumor growth and invasiveness in a syngeneic model of rat prostate cancer using a Dunning R3227 cell line over-expressing rat uPA. Male Copenhagen rats were inoculated s.c. with experimental cells into the right flank and continuously infused i.p. with either vehicle alone or uPA inhibitor for 2 to 3 weeks. Animals were killed at timed intervals and evaluated for the development of tumor growth and metastasis. Serum from these animals was collected to examine any signs of nephrotoxicity. Control animals receiving vehicle alone developed large tumors at the site of inoculation as well as macroscopic metastases in the lungs, kidney, spleen and lymph nodes. In contrast, experimental animals receiving uPA inhibitor showed a marked decrease in primary tumor volume and weight as well as in the development of tumor metastases. The occasional tumor metastases observed after infusion of B-428 were significantly smaller than those observed in vehicle controls. These effects of B-428 were found to be dose-dependent without any adverse effects on the renal function of experimental animals. These studies demonstrate that uPA-specific inhibitors can decrease primary tumor volume and invasiveness as well as metastasis in a model of prostate cancer where uPA has been implicated as a major pathogenetic factor.

Prostate carcinoma is one of the most common malignancies affecting males, resulting in a high rate of morbidity and mortality. This hormone-dependent malignancy is characteristically associated with a high incidence of osteoblastic skeletal lesions. However, osteolytic lesions invariably accompany blastic ones. In the current study, we assessed the role of parathyroid hormone-related peptide (PTHRP), a potent bone-resorbing agent, in contributing to bone breakdown and prostatic skeletal metastasis using a syngeneic rat prostate cancer model. The full-length cDNA encoding rat PTHRP was subcloned as a Hind III insert in the sense orientation into the mammalian expression vector pRc-CMV to generate the expression vector pRc-PTHRP-S. Both control and experimental plasmids were stably transfected into low PTHRPproducing Dunning R3227, Mat Ly Lu rat prostate cancer cells. Prostatic cancer has a high propensity to metastasize to the skeleton, and skeletal metastatic disease is a major cause of morbidity (Chiarodo et al., 1991). Osteoblastic lesions are characteristic of the bone disease caused by prostate cancer, and indeed, prostate cancer is one of the most common cancers associated with osteoblastic bone disease. Several potential mediators of the osteoblastic response in bone have been described, including transforming growth factor beta (TGF-␤), fibroblast growth factor (FGF), bone morphogenetic protein (BMP) and the NH 2 -terminal region of urokinase (Harris et al., 1994;Rabbani et al., 1990Rabbani et al., , 1992. Many, if not all, skeletal lesions of prostate cancer, however, also include an osteolytic component (Franks, 1973). Both histological and biochemical evidence support the presence of osteolysis in association with prostate cancer metastases to bone; nevertheless, this component of the disease has received relatively little attention (Franks, 1973;Takeuchi et al., 1996). The most common skeletal response to cancer metastases in general is osteolysis, and the mechanisms underlying this response are now beginning to be defined. The mediators of osteolysis appear to include cytokines, growth factors and possibly prostaglandins released either by invading tumor cells or by host cells in bone in response to invading tumor cells (Jilka et al., 1992;Bonjour and Rizzoli, 1989;Francini et al., 1993).Parathyroid hormone-related peptide (PTHRP) is a moiety which was first discovered as a mediator of hypercalcemia associated with malignancy (Henderson et al., 1989;Suva et al., 1987;Asadi et al., 1996). Three PTHRP isoforms exist in humans, which are 139, 141 and 173 amino acids in length. All isoforms share homology at the NH 2 terminus with the NH 2 region of parathyroid hormone (PTH) (Moseley et al., 1987; Steward et al, 1987;Strewler et al., 1987;Rabbani et al., 1986). This homology facilitates interaction with a common PTH/PTHRP receptor and serves as the molecular basis for similar biological actions of PTH and PTHRP (Jüeppner et al., 1991;Abou-Samra et al., 1992). Included in these actions is the capacity to...