Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects are not completely clear. In this study, we assessed whether a DD combinatorial regimen of low-dose cisplatin and paclitaxel produces superior immune-mediated efficacy when compared to a maximum-tolerated dose (MTD) regimen, in treating platinum-resistant ovarian cancer as modeled in mice. Immune responses generated by the DD regimen were identified with regard to the immune cell subset responsible for the antitumor effects observed. The DD regimen was less toxic to the immune system, reduced immunosuppression by the tumor microenvironment, and triggered recruitment of macrophages and tumor-specific CD8+ T cell responses to tumors (as determined by IL-2 and IFN-γ secretion). In this model, we found that the DD regimen exerted greater therapeutic effects than the MTD regimen, justifying its further clinical investigation. Fourteen patients with platinum-resistant relapse of ovarian cancer received DD chemotherapy consisting of weekly carboplatin (AUC2) and paclitaxel (60-80 mg/m2) as the third or fourth-line treatment. Serum was collected over the course of treatment and serial IFN-γ and IL-2 levels were used to determine CD8+ T cell activation. Of the 4 patients with disease control, 3 had serum levels of IL-2 and IFN-γ associated with cytotoxic CD8+ T cell activity. The therapeutic effect of the DD chemotherapy relied on the preservation of the immune system and the treatment-mediated promotion of tumor-specific immunity, especially the antitumor CD8+ T cell response. Since the DD regimen controlled drug-resistant disease through a novel immune mechanism, it may offer a fine strategy for salvage treatment.

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Bortezomib, a proteasome inhibitor, is a chemotherapeutic drug that is commonly used to treat a variety of human cancers. The antitumor effects of bortezomib-induced tumor cell immunogenicity have not been fully delineated. In this study, we examined the generation of immune-mediated antitumor effects in response to treatment by bortezomib in a murine ovarian tumor model. We observed that tumor-bearing mice that were treated with bortezomib had CD8+ T cell-mediated inhibition of tumor growth. Furthermore, the comparison of tumor cell-based vaccines that were produced from tumor cells treated or untreated with bortezomib showed vaccination with drug-treated tumor cell-based vaccines elicited potent tumor-specific CD8+ T cell immune response with improved therapeutic antitumor effect in tumor-bearing mice. Conversely, the untreated tumor cell-based vaccines led to no appreciable antitumor response. Treatment of tumor cells with bortezomib led to the upregulation of Hsp60 and Hsp90 on the cell surface and promoted their phagocytosis by dendritic cells (DCs). However, cell surface expression of Hsp60, instead of Hsp90, is the more important determinant of whether bortezomib-treated tumor cells can generate tumor-specific CD8+ T cells. CD11c+ DCs that were treated with bortezomib in vitro had enhanced phagocytic activities. In addition, CD11c+ DCs from bortezomib-treated tumor-bearing mice had increased maturation. At lower concentrations, bortezomib had no inhibitory effects on T cell proliferation. Taken together, our data indicate that bortezomib can render tumor cells immunogenic by upregulating the cell surface expression of heat shock protein 60 and heat shock protein 90, as well as improve DC function, which results in potent immune-mediated antitumor effects.

Allopurinol is a xanthine oxidase inhibitor with poor solubility and permeability, which severely limit its drug absorption following the administration of some dosage forms, such as tablets and rectal suppositories. To improve the physicochemical properties, three cocrystals of allopurinol with isonicotinamide (ALP-INA), piperazine (ALP-PIP), and 2,4-dihydroxybenzoic acid (ALP-24DHBZA) were successfully prepared by a slurry or liquid-assisted grinding method. The obtained cocrystal materials were characterized by single-crystal X-ray diffraction, powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analyses and were subjected to dynamic vapor sorption, dissolution, and membrane permeability studies. ALP-INA showed solubility and diffusion/membrane permeability similar to those of the parent drug. In contrast, ALP-PIP exhibited improved diffusion/membrane permeability, and ALP-24DHBZA exhibited improved dissolution behavior, respectively. These results suggest that ALP-PIP and ALP-24DHBZA have the potential to be developed as new, more efficient formulations of allopurinol.

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