Glenn T. Miller

PT-100, a Small Molecule Dipeptidyl Peptidase Inhibitor, Has Potent Antitumor Effects and Augments Antibody-Mediated Cytotoxicity via a Novel Immune Mechanism

The amino boronic dipeptide, PT-100 (Val-boro-Pro), a dipeptidyl peptidase (DPP) inhibitor, has been shown to up-regulate gene expression of certain cytokines in hematopoietic tissue via a high-affinity interaction, which appears to involve fibroblast activation protein. Because fibroblast activation protein is also expressed in stroma of lymphoid tissue and tumors, the effect of PT-100 on tumor growth was studied in mice in vivo. PT-100 has no direct cytotoxic effect on tumors in vitro. Oral administration of PT-100 to mice slowed growth of syngeneic tumors derived from fibrosarcoma, lymphoma, melanoma, and mastocytoma cell lines. In WEHI 164 fibrosarcoma and EL4 and A20/2J lymphoma models, PT-100 caused regression and rejection of tumors. The antitumor effect appeared to involve tumor-specific CTL and protective immunological memory. PT-100 treatment of WEHI 164-inoculated mice increased mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells. The role of innate activity was further implicated by observation of significant, although reduced, inhibition of WEHI 164 and A20/2J tumors in immunodeficient mice. PT-100 also demonstrated ability to augment antitumor activity of rituximab and trastuzumab in xenograft models of human CD20+ B-cell lymphoma and HER-2+ colon carcinoma where antibody-dependent cytotoxicity can be mediated by innate effector cells responsive to the cytokines and chemokines up-regulated by PT-100. Although CD26/DPP-IV is a potential target for PT-100 in the immune system, it appeared not to be involved because antitumor activity and stimulation of cytokine and chemokine production was undiminished in CD26−/− mice.

Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin.

Palifosfamide, the DNA-alkylating metabolite of ifosfamide (IFOS), has been synthesized as a stabilized tris or lysine salt and found to have preclinical and clinical antitumor activity. Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resulting from variable prodrug activation, resistance and toxicities of metabolic byproducts, acrolein and chloroacetaldehyde. Palifosfamide represents an effective alternative to IFOS and other DNA-alkylating prodrugs. The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague–Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P<0.05) by greater than 80% with 17% complete antitumor responses and up to three-fold increase in time to three tumor doublings over controls. Median survival in the P388-1 (P<0.001) model was increased by 9 days over controls. Oral bioavailability in rats was 48–73% of parenteral administration, and antitumor activity in mice was equivalent by both routes. Treatment with palifosfamide-tris combined with docetaxel or doxorubicin at optimal regimens resulted in complete tumor regression in 62–75% of mice. These studies support investigation of stabilized palifosfamide in human cancers by parenteral or oral administration as a single agent and in combination with other approved drugs. The potential for clinical translation of the cooperative interaction of palifosfamide-tris with doxorubicin by intravenous administration is supported by results from a recent randomized Phase-II study in unresectable or metastatic soft-tissue sarcoma.