Multiple myeloma (MM) is an incurable plasma cell malignancy. The recent successes of the proteasome inhibitor bortezomib in MM therapy have prompted investigations of its efficacy in combination with other anticancer agents.

Cryptosporidium parvum infection of T-cell receptor alpha (TCR-␣)-deficient mice results in a persistent infection. In this study, treatment with a polyamine analogue (SL-11047) prevented C. parvum infection in suckling TCR-␣-deficient mice and cleared an existing infection in older mice. Treatment with putrescine, while capable of preventing infection, did not clear C. parvum from previously infected mice. These findings provide further evidence that polyamine metabolic pathways are targets for new anticryptosporidial chemotherapeutic agents.

Enterocytozoon bieneusi is the most common cause of chronic diarrhea in individuals with human immunodeficiency virus infection or AIDS, and there is no effective therapy. The inhibitory activities of polyamine analogues (PG-11157, PG-11158, and PG-11302) against E. bieneusi infection were evaluated in SCID mice preconditioned with anti-gamma interferon monoclonal antibody intraperitoneally (i.p.). Mice were challenged orally with 10 4 E. bieneusi spores, and groups of mice were treated orally or i.p. 14 days later for 7 days. The inhibitory activities of the drugs against infection were determined by enumerating the E. bieneusi spores in feces three times a week by an immunofluorescence assay. Immunohistochemistry staining confirmed the infection within enterocytes. Oral administration of the analogues PG-11157 (at 150 or 75 mg/kg of body weight/day) and PG-11302 (at 250 mg/kg/day) had significant inhibitory activity (96.2 to 99.6%) that was slightly better than that of fumagillin (1 mg/kg/day; 93.7%). The inhibitory activity with i.p. injection was significant only with PG-11302 at 20 mg/kg/day. While the treatments considerably reduced the levels of spore excretion, neither polyamine analogues nor fumagillin was able to completely eliminate E. bieneusi, as excretion reappeared within 7 days after the end of treatment. Drug toxicity was apparent during treatment, but it disappeared at the end of treatment. These results warrant further examination of the analogues PG-11157 and PG-11302.While it has been recognized as a disease-causing agent in humans since 1985, little progress was made in the diagnosis or treatment of Enterocytozoon bieneusi over the last two decades because of a lack of laboratory tools and reagents, as well as the inability to propagate the parasite in cell culture or in animals. The lack of immune reagents and a spore size similar to that of most bacteria have made identification, concentration, and purification of the organism difficult. Consequently, many investigators have used clinically less significant, surrogate species. Current therapies for microsporidia, like albendazole, are ineffective against E. bieneusi. Fumagillin is not curative and is known to cause thrombocytopenia in AIDS patients; it is also toxic when it is administered systemically. There is a clear need for therapy for E. bieneusi infections.Our laboratories have recently made significant discoveries in several pivotal areas, which have contributed to the progress on E. bieneusi research. These discoveries are as follows. (i) We have developed molecular diagnostic tools that are of help with investigation of the role of E. bieneusi in children (29,30).(ii) By using the macaque model, the relationship between immune dysfunction in the gastrointestinal tract due to simian immunodeficiency virus infection or simian AIDS and the persistence of E. bieneusi infection in the immunodeficient host were defined (25, 26). (iii) Methods for the purification of E. bieneusi spores from the stools of infected patients were develope...

<div>Abstract<p>Multiple myeloma (MM) is an incurable plasma cell malignancy. The recent successes of the proteasome inhibitor bortezomib in MM therapy have prompted investigations of its efficacy in combination with other anticancer agents. Polyamines play important roles in regulating tumor cell proliferation and angiogenesis and represent an important therapeutic target. CGC-11093 is a novel polyamine analogue that has completed a phase I clinical trial for the treatment of cancer. Here, we report that CGC-11093 selectively augments the <i>in vitro</i> and <i>in vivo</i> antimyeloma activity of bortezomib. Specifically, the combination of CGC-11093 and bortezomib compromised MM viability and clonogenic survival, and increased drug-induced apoptosis over that achieved by either single agent. Xenografts of MM tumors treated with this combination had marked increases in phospho-c-Jun-NH₂-kinase (JNK)-positive cells and apoptosis, and corresponding reductions in tumor burden, tumor vasculature, and the expression of proliferating cell nuclear antigen and the proangiogenic cytokine vascular endothelial growth factor. Furthermore, inhibition of JNK with a pharmacologic inhibitor or by selective knockdown blunted the efficacy of CGC-11093 and bortezomib. Therefore, CGC-11093 enhances the anticancer activity of bortezomib by augmenting JNK-mediated apoptosis and blocking angiogenesis. These findings support the study of the use of the combination of bortezomib and CGC-11093 in MM patients that fail to respond to frontline therapy. [Cancer Res 2008;68(12):4783–90]</p></div>

Supplementary Methods and Figure 1 from The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib