A metronomic schedule of cyclophosphamide combined with PEGylated liposomal doxorubicin....

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Int J Pharm. 2008 Apr 2;353(1-2):65-73. Epub 2007 Nov 17.

Shiraga E, Barichello JM, Ishida T, Kiwada H.
of Pharmacokinetics and Biopharmaceutics, Subdivision of
Biopharmaceutical Science, Institute of Health Biosciences, The
University of Tokushima, Tokushima, Japan.
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
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.