A metronomic schedule of cyclophosphamide combined with PEGylated liposomal doxorubicin has a highly antitumor effect in an experimental pulmonary metastatic mouse model.

Metronomic chemotherapy is a novel approach to the control of advanced cancer, as it appears to preferentially inhibit endothelial cell activity in the growing vasculature of tumors. Doxorubicin-containing sterically stabilized liposomes (DXR-SL) accumulate in large amounts in tumor tissue, resulting in enhanced antitumor effects of the encapsulated DXR. In the present study, it was hypothesized that metronomic chemotherapy may further augment the accumulation of DXR-SL, improving its therapeutic efficacy. This study tests the antitumor efficacy for the combination of a metronomic cyclophosphamide (CPA)-dosing schedule with sequential intravenous injections of DXR-SL in the treatment of lung metastatic B16BL6 melanoma-bearing mice. Three dosing schedules for the combination of metronomic CPA injections (s.c. 170 mg/kg every 6 days) plus either a low or a high dose of DXR-SL (i.v. 1 or 5 mg/kg every 6 days) were set: Schedule I, DXR-SL was given 3 days before the first CPA treatment; Schedule II, DXR-SL and CPA were given simultaneously; and, Schedule III, DXR-SL was given 3 days after the first CPA treatment. Lung weight and median survival time (MST) were evaluated. As expected, both the dosing schedule as well as the dose of DXR-SL improved therapeutic efficacy. Schedule I with the low DXR dose and Schedule II with the low or high DXR dose significantly increased MST, compared with regular metronomic CPA therapy. Under the dosing schedules (Schedule I with the low DXR dose and Schedule II with the high DXR), there was a strong relationship between increased MST and decreased lung weight. However, Schedule I with high DXR dose resulted in significantly lower lung weights, but did not increase MST, suggesting that chemotherapy may result in increased toxicity in some conditions. Although treatment regimens require optimization, the results of the present study may prove useful in further explorations of combining metronomic chemotherapy with liposomal anticancer drugs in the treatment of solid tumors.

Synergistic antitumor activity of metronomic dosing of cyclophosphamide in combination with doxorubicin-containing PEGylated liposomes in a murine solid tumor model.

Cyclophosphamide (CPA) and doxorubicin (DXR)-containing sterically stabilized liposomes (DXR-SL) have a proven clinical activity. We propose that a metronomic CPA dosing schedule enhances accumulation of DXR-SL in solid tumors, because it causes apoptosis in the endothelial cells of the growing tumor vasculature and thereby may increase the permeability of the tumor microvessels. To establish the validity of this hypothesis we investigated the therapeutic benefits of metronomic CPA dosing (p.o.) combined with DXR-SL (i.v.) in a Lewis lung carcinoma, subcutaneously growing in C57BL/6 mouse. The metronomic CPA dosing clearly promoted accumulation and subsequent deep diffusion of SL in the solid tumor as a result of rather a transient increase in the density of CD31(+)-microvessels, which shows high permeability to SL. It appears that the enhancing effect of metronomic CPA dosing is strongly dependent on the dose of CPA as well as on the time at which the treatment was initiated. Our study indicates that the use of metronomic chemotherapy combined with nanocarriers may be of significant clinical and practical importance in treating intractable solid tumors.