Abstract
We previously developed a novel and effective therapy for hormone-refractory prostate cancer using the agents estramustine and etoposide. Although neither of these agents alone is effective in the treatment of advanced, hormone-refractory prostate cancer, we predicted their activity when used in combination based on preclinical assays, and then demonstrated their effectiveness in a phase I-II clinical trial, where they were shown to produce a 50% complete and partial response rate in patients with bidimensionally measurable disease. In preclinical studies, we had demonstrated that estramustine and etoposide interact with the nuclear matrix, which is the site of DNA replication. Expanding these investigations, we determined that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a microtubule inhibitor, interacts with estramustine and etoposide, and the combination of these three agents had significant preclinical activity against androgen-independent prostate cancer cells. These studies led us to conduct a phase II clinical trial of paclitaxel, estramustine, and etoposide in patients with hormone-refractory prostate cancer. Preliminary results demonstrate that this is an active regimen, with 57% of patients demonstrating a response to therapy as measured by a decrease in pretreatment prostate-specific antigen levels of greater than 50%.
Publication types
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Clinical Trial
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Clinical Trial, Phase I
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Clinical Trial, Phase II
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / pathology
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Administration, Oral
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Alopecia / chemically induced
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Animals
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Antineoplastic Agents, Hormonal / administration & dosage*
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Antineoplastic Agents, Hormonal / adverse effects
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Antineoplastic Agents, Hormonal / therapeutic use*
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Antineoplastic Agents, Phytogenic / administration & dosage*
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Antineoplastic Agents, Phytogenic / adverse effects
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / adverse effects
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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DNA Replication / drug effects
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DNA, Neoplasm / drug effects
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Disease Progression
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Drug Administration Schedule
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Drug Resistance, Neoplasm*
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Drug Screening Assays, Antitumor
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Estramustine / administration & dosage*
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Estramustine / adverse effects
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Etoposide / administration & dosage*
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Etoposide / adverse effects
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Follow-Up Studies
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Humans
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Infusions, Intravenous
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Male
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Microtubules / drug effects
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Nuclear Matrix / drug effects
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Paclitaxel / administration & dosage*
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Paclitaxel / adverse effects
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Prostate-Specific Antigen / analysis
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / pathology
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Rats
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Remission Induction
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents, Hormonal
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Antineoplastic Agents, Phytogenic
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DNA, Neoplasm
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Estramustine
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Etoposide
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Prostate-Specific Antigen
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Paclitaxel