Aclarubicin is an
anthracycline antibiotic that differs from
doxorubicin in its structure, mechanism of action, and preclinical toxicity profile, especially its reduced
cardiotoxicity. We therefore conducted a side-by-side in vivo and in vitro trial of this agent in metastatic
breast-cancer patients and their biopsied
tumor specimens, respectively.
Aclarubicin (100 mg/m2) was given by
intravenous infusion every 3 weeks to 22 patients with objectively measurable metastatic
breast cancer, 15 of whom had not previously received
doxorubicin. The dose-limiting toxicity consisted primarily of
leukopenia and severe
nausea and
vomiting. No objective response was observed in the 19 evaluable patients. After
disease progression, 10 of the 15
doxorubicin-naive patients were treated with
doxorubicin; 6 patients achieved a partial response, including 4 who responded to
doxorubicin alone and 2 who responded to
doxorubicin in combination with
thiotepa and
vinblastine.
Tumor specimens were obtained from 14 of the 22 patients prior to the start of
therapy and were tested for in vitro sensitivity to
aclarubicin and
doxorubicin using a soft
agar colony-forming assay. Adequate colony growth occurred in 9 of 14 cultured
tumor specimens. All 9 specimens, including 3 obtained from
doxorubicin-naive patients, demonstrated in vitro resistance to
aclarubicin. In all, 1 of 3 specimens taken from
doxorubicin-naive patients demonstrated in vitro sensitivity to
doxorubicin, whereas 6
tumor specimens obtained from patients who had undergone prior
doxorubicin therapy demonstrated in vitro resistance. The patient whose
tumor demonstrated in vitro
doxorubicin sensitivity responded to a
doxorubicin regimen after failing
aclarubicin treatment; in vitro
doxorubicin resistance correlated with clinical resistance in all cases. We conclude that
aclarubicin is inactive in metastatic
breast cancer at the dose and schedule used. Side-by-side in vivo and in vitro trials are feasible and could be useful in the development of investigational agents with activity greater than that of
aclarubicin and, particularly, in the evaluation of analogs of clinically active drugs.