Metronomic cyclophosphamide and metformin inhibited tumor growth and repopulated tumor-infiltrating lymphocytes in an experimental carcinoma model.

Metformin is a widely used antidiabetic biguanide. Retrospective data demonstrated the association of metformin use with survival benefit in multiple tumor types. Interest in repurposing metformin to treat cancer has not been translated into encouraging clinical benefit. In animal models, metformin activated cytotoxic T cells and exerted an immune-mediated anticancer effect. The current research was conducted to investigate the possible therapeutic benefit of metformin in combination with metronomic cyclophosphamide in an experimental cancer model. Ehrlich ascites carcinoma was injected into the subcutaneous tissue to induce solid tumors in syngeneic mice. Exponential solid tumor growth ensued and was effectively arrested with the administration of a cytotoxic dose of parenteral cyclophosphamide. Alternatively, oral metformin and continuous, low-dose cyclophosphamide significantly inhibited tumor growth relative to untreated mice. The drug combination was well tolerated. Histopathological examination of the tumor showed an increased number of tumor-infiltrating lymphocytes and enhanced expression of granzyme B by this drug combination. The current data suggests a potential role of metformin and metronomic chemotherapy that warrants further investigation.

Ki67 and CD31 Differential Expression in Cutaneous T-Cell Lymphoma and Its Mimickers: Association with Clinicopathological Criteria and Disease Advancement.

BACKGROUND: Cell proliferation and angiogenesis are important in progression of cancerous processes. Differentiating cutaneous T-cell lymphoma (CTCL) from its mimicking dermatoses and prognosticating it are challenging. AIM: This study assesses cell proliferation and angiogenesis in different CTCL subtypes using immunohistochemistry (IHC) for Ki67 and CD31 to testify their usability in differentiating CTCL from mimicking dermatoses and discriminating CTCL subtypes from each other with correlation to clinicopathological parameters and disease advancement. PATIENTS AND METHODS: IHC for Ki67 and CD31 were applied to skin biopsies from 81 patients divided into CTCL (n=59) and dermatoses (n=22) groups. Hot-spot analysis was used to score Ki67 and CD31 microvascular density (MVD) semiquantitatively. Statistical analysis was performed to compare Ki67 index and MVD between CTCL and dermatoses. CTCL subgroups were compared to each other. Ki67 index and CD31 were compared to age, gender, skin and nodal involvement, blood tumor burden and TNMB stage. RESULTS AND CONCLUSION: There were significant differences in proliferation index and MVD between dermatoses and CTCL, and between dermatoses and all CTCL subtypes with exception of Ki67 in early mycosis fungoides (MF) and CD31 in patch lesions. Increased cell proliferation and MVD were significantly associated with older age, T3 and 4 skin involvement, significant nodes (N1-3), positive blood tumor burden (B1,2) in CTCL and TNMB stage of MF. Both markers differentiated significantly late from early MF, classic MF from its variants and non-MF CTCL from total MF, but not from late MF. In conclusion, Ki67 and CD31 expression in skin biopsies using IHC reproduces the role of proliferation and angiogenesis in the differential diagnosis and prognostication of CTCL being expressed at higher levels in aggressive than indolent CTCL. Therapeutic targeting of cell proliferation and angiogenesis may improve patient's outcome in CTCL. Usability of these markers into patient's stratification should be considered in further studies.