elsamicin-a and Breast-Neoplasms

We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients.. A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF.. The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm.. The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.

Topics: Adenine; Adult; Aged; Aminoglycosides; Analysis of Variance; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Imides; Isoquinolines; Melphalan; Middle Aged; Naphthalimides; Neoplasm Staging; Organophosphonates; Prospective Studies; Survival Analysis; Trimetrexate

To test the antitumor activity of Elsamitrucin in metastatic cancer of the breast, colon and rectum, non-small cell lung and ovary.. Eligibility required histologically proven cancer. Patients with colorectal or non-small cell lung cancer could not have received prior chemotherapy. Patients were entered if WHO PS was < or = 2 and organ functions were normal. Treatment consisted of Elsamitrucin 25 mg/m2/week given as a 5-10 min infusion for at least 3-6 weekly doses.. One hundred and five patients entered the studies, 97 were eligible, 94 are evaluable for toxicity and 75 for response. Toxicity mainly consisted of mild nausea/vomiting, and less frequently reversible hepatotoxicity and malaise. No objective responses were seen.. Elsamitrucin at this dose and schedule is not an active drug in metastatic breast cancer, colorectal cancer, non-small cell lung cancer or ovarian cancer.

Topics: Adolescent; Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms

The in vitro activity of elsamicin A (ELS) was investigated compared with that of doxorubicin (DX) on two sensitive breast cancer cell lines: one estrogen receptor-positive (ER+, MCF7) and one estrogen receptor-negative (ER-, MDA-MB-231) line, and on a DX-resistant subline (MCF7DX). The activity of the two drugs was also investigated on 19 clinical breast cancer specimens from untreated patients. The drugs were tested at pharamcologically relevant concentrations, as calculated from the area under the curve for a 3 h exposure to the lethal dose producing 10% mortality (LD10) in mice, and at 10- and 100-fold concentrations. In DX-sensitive lines, a greater inhibition of RNA and DNA precursor incorporation, as well as of cell proliferation, was caused by ELS than by DX. Moreover, the antiproliferative effect was 10-fold higher in the ER+ MCF7 than in the ER- MDA-MB-231 cell line (IC50: 0.25 versus 0.21 micrograms/ml). ELS was cross-resistant to DX in the MCF7DX subline. In clinical specimens, effects on DNA precursor incorporation were more often observed for ELS than for DX at the same drug concentrations. The in vitro sensitivity to ELS was more pronounced for ER+ than for ER- tumors: minimal inhibiting concentrations of the drug were 0.1 and 3.5 micrograms/ml, respectively, in the two groups. If confirmed in a larger series of human breast tumors, these in vitro results would indicate a promising role for ELS in clinical treatment, mainly of ER+ breast cancer patients.

Topics: Adenocarcinoma; Aminoglycosides; Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Benzopyrans; Breast Neoplasms; Cell Division; DNA, Neoplasm; Doxorubicin; Drug Resistance; Female; Glycosides; Humans; Mice; Receptors, Estrogen; RNA, Neoplasm; Tumor Cells, Cultured