Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer with metronomic UFT + CP

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Cancer Res. 2006 Apr 1;66(7):3386-91.

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Munoz R, Man S, Shaked Y, Lee CR, Wong J, Francia G, Kerbel RS.

Sunnybrook and Women's College Health Sciences Centre S-217, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
Metronomic
antiangiogenic chemotherapy, the prolonged administration of relatively
low drug doses, at close regular intervals with no significant breaks,
has been mainly studied at the preclinical level using single
chemotherapeutic drugs, frequently in combination with a targeted
antiangiogenic drug, and almost always evaluated on primary localized
tumors. We tested a "doublet" combination metronomic chemotherapy
treatment using two oral drugs, UFT, a 5-fluorouracil (5-FU) prodrug
administered by gavage, and cyclophosphamide, for efficacy and toxicity
in a new mouse model of advanced, terminal, metastatic human breast
cancer.
 
The optimal biological dose of each drug was first determined
by effects on levels of circulating endothelial progenitor cells as a
surrogate marker for angiogenesis, which was assessed to be 15 mg/kg
for UFT and 20 mg/kg for cyclophosphamide. A combination treatment was
then evaluated in mice with advanced metastatic disease using a
serially selected metastatic variant of the MDA-MB-231 breast
cancer-cell line, 231/LM2-4. UFT or cyclophosphamide treatment showed
only very modest survival advantages whereas a combination of the two
resulted in a remarkable prolongation of survival, with no evidence of
overt toxicity despite 140 days of continuous therapy, such that a
significant proportion of mice survived for over a year. In contrast,
this striking therapeutic effect of the combination treatment was not
observed when tested on primary orthotopic tumors. We conclude that
combination oral low-dose daily metronomic chemotherapy, using
cyclophosphamide and UFT, is superior to monotherapy and seems to be a
safe and highly effective experimental antimetastatic therapy, in this
case, for advanced metastatic breast cancer.