estramustine and Neoplasms

This phase I/II study evaluated the safety of the combination of irinotecan, docetaxel, and estramustine for selected advanced solid tumors and also obtained initial efficacy data. Twenty-two patients were enrolled in the study. The regimen consisted of docetaxel 30 mg/m(2) and irinotecan 60 mg/m(2) both given intravenously on days 1 and 8 every 21 days in combination with escalating doses of estramustine (500 mg/m(2)/day escalated to 750 mg/m(2)/day on days 0, 1, 2, 7, 8, and 9 given every 21 days) during phase I. Dose escalation was continued until the maximum planned dose level of estramustine (750 mg/m(2)/day) was reached. After the appropriate phase II dose of estramustine was found additional patients were enrolled. Twenty-one of the 22 patients were evaluable for toxicity and 17 for tumor response. The recommended phase II dose of estramustine was found to be 750 mg/m(2)/day orally on days 0, 1, 2, 7, 8, and 9 given every 21 days. Hematologic toxicity was fairly mild, with only one episode of grade 3 neutropenia. Diarrhea was the most common nonhematologic toxicity with grade 3 toxicity occurring in five of 21 patients. Only one episode of venous thrombosis was observed. Objective response rate was 15.8%, overall clinical benefit rate was 63%, and median time to progression was 15 weeks. Estramustine in combination with the doublet of docetaxel and irinotecan is a well-tolerated regimen with minimal hematologic toxicity, mild to moderate nonhematologic toxicity, and promising initial antitumor activity in previously treated patients with advanced solid tumors.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Estramustine; Female; Humans; Irinotecan; Male; Middle Aged; Neoplasms; Taxoids; Treatment Outcome

Anti-tubulin couplets have activity in hormone-resistant prostate cancer. This study was designed to define the dose-limiting toxicity (DLT) and recommended phase II dose (RPTD) of the unique triplet combination of paclitaxel, estramustine phosphate (EMP) and vinorelbine (Pacl-E-Vin). Patients with advanced malignancies who had failed standard therapy, ECOG performance status (PS 0-2) and adequate organ function were included. Dose of EMP was fixed at 300 mg/m2/dose p.o. t.i.d. on days 1-3 and 8-10. Vinorelbine dose was 20 mg/m2/day i.v. on days 3 and 10. Paclitaxel was dose escalated from 40 to 50 mg/m /day i.v. on days 3 and 10. Cycles were repeated every 3 weeks. Twelve adults (median age 72) were entered on this study. Primary tumors included prostate (n=7), cervix (n=2), melanoma (n=1), colon (1) and lung with synchronous prostate cancer (n=1). Nine patients had received no prior chemotherapy, one had received a prior regimen and two had received two or more prior regimens. Of four evaluable patients at dose level 1, one patient had grade 3 neutropenia leading to the day 10 dose being withheld. Of five evaluable patients at dose level 2, there was one DLT (febrile neutropenia) and two grade 3 neutropenias leading to the day 10 dose being withheld. One patient had a lower extremity deep vein thrombosis. Other side effects were mild and reversible. Nine patients were evaluable for efficacy: three with prostate cancer had a greater than 50% prostate-specific antigen (PSA) response, and a patient with synchronous prostate and lung cancer had a greater than 50% PSA response. We conclude that the DLT of Pacl-E-Vin is neutropenia. RPTD is vinorelbine 20 mg/m2, paclitaxel 40 mg/m2, both administered on days 3 and 10, and EMP 900 mg/m2/day on days 1-3 and 8-10, q3w. Dose omission at day 10 followed by 20% dose reduction of paclitaxel and vinorelbine is recommended in the event of grade 3 neutropenia. Activity in hormone-refractory prostate cancer is promising and warrants phase II evaluation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Delivery Systems; Estramustine; Female; Humans; Male; Middle Aged; Neoplasms; Paclitaxel; Tubulin; Vinblastine; Vinorelbine

We sought to determine the tolerance of estramustine phosphate (EMP) combined with a 3-hour paclitaxel infusion in women with solid paclitaxel-pretreated solid tumors. Paclitaxel pharmacology was to be studied at the recommended phase II dose.. Paclitaxel was administered to cohorts of at least three assessable patients at doses of 150, 180, 210, and 225 mg/m2, while EMP was given at 900 and 1,200 mg/m2/d in divided doses orally for 2 days preceding and on the day of paclitaxel. The pharmacologic study was performed at 225 mg/m2 paclitaxel given in the absence and 3 weeks later in the presence of EMP 900 mg/m2/d.. Thirty-eight patients received a total of 178 courses. Grade 3 nausea, vomiting, and diarrhea were common at EMP 1,200 mg/m2 and paclitaxel 225 mg/ m2; this was considered the maximum-tolerated dose. Since these toxicities appeared related to EMP, the pharmacologic study used a dose of 900 mg/m2 of this agent with 225 mg/m2 paclitaxel. Antitumor activity was documented against breast and ovarian cancers at all levels. Paclitaxel pharmacokinetics without and with EMP did not differ.. EMP 900 mg/m2 for 3 days and 225 mg/m2 paclitaxel by 3-hour infusion are well tolerated; antitumor activity was seen in women with paclitaxel-pretreated solid tumors. This apparent enhancement of antitumor effects is unlikely to be mediated by P-glycoprotein.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Interactions; Estramustine; Female; Humans; Infusions, Intravenous; Middle Aged; Neoplasms; Paclitaxel

Estramustine phosphate is a unique antimitotic agent that binds to tubulin and microtubule-associated proteins. Preclinically, estramustine combined with other microtubule inhibitors, like vinblastine or paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), produced additive or greater antimitotic and cytotoxic effects. Clinically, the estramustine/vinblastine combination has significant activity in hormone-refractory prostate cancer. We have begun a phase I study of paclitaxel by 96-hour continuous infusion every 3 weeks combined with daily oral estramustine (600 mg/m2). Eighteen patients with refractory solid tumors have received paclitaxel doses ranging from 80 to 140 mg/m2. Grade 3 or 4 granulocytopenia occurred in one of seven and two of four patients treated at the 120- and 140-mg/m2 dose levels, respectively. The latter two patients experienced grade 3 mucositis and had mean plasma paclitaxel levels exceeding 0.1 mumol/L. Other toxicities, principally nausea and hepatic function abnormalities, have been mild. The apparent steady-state concentrations of paclitaxel 100 and 120 mg/m2 administered with estramustine are similar to those reported for single-agent paclitaxel administered as a 96-hour infusion at doses of 100 and 120 mg/m2. In contrast, at the 140 mg/m2 dose level, paclitaxel concentrations increased throughout the infusion, and steady state was not reached in three of the four patients treated. Objective responses have been observed in two of three patients with adenocarcinoma of the esophagus and in two patients with hormone-resistant prostate cancer and measurable soft tissue metastases. Two additional patients with prostate cancer have been treated with the estramustine/paclitaxel combination, one achieving a major response and the other stable disease. The recommended phase II dose for 96-hour infusional paclitaxel with daily oral estramustine is at least 120 mg/m2. Studies to determine the effect of estramustine on paclitaxel pharmacokinetics are continuing. The antitumor activity observed merits phase II studies of this combination in hormone-resistant prostate cancer and other malignancies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Female; Humans; Male; Neoplasms; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms

Shp2 protein tyrosine phosphate (PTP) is a novel target for anticancer drug discovery. We identified estramustine phosphate as a Shp2 PTP inhibitor from the National Cancer Institute Approved Oncology Drug set. A focused structure-activity relationship study indicated that the 17-phosphate group is required for the Shp2 PTP inhibitor activity of estramustine phosphate. A search for estramustine phosphate analogs led to identification of two triterpenoids, enoxolone, and celastrol, having Shp2 PTP inhibitor activity. With the previously reported PTP1B inhibitor trodusquemine, our study reveals steroids and triterpenoids with negatively charged phosphate, carboxylate, or sulfonate groups as novel pharmacophores of selective PTP inhibitors.

Topics: Antineoplastic Agents, Hormonal; Estramustine; Humans; Models, Molecular; Neoplasms; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Structure-Activity Relationship; Triterpenes

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Drug Synergism; Estramustine; Female; Humans; Neoplasms; Ovarian Neoplasms; Paclitaxel; Taxoids

Estramustine (EM), an antimicrotubule agent, binds microtubule-associated proteins, causes spindle disassembly, and arrests cells at the late G2/M phase of the cell cycle. Since cells in the G2/M phase are the most radiosensitive and some human cancer cells contain high level of EM-binding protein, experiments were carried out to determine whether radiation sensitization could be obtained in human carcinoma cells.. Cells containing a high level of EM-binding protein such as prostate carcinoma (DU-145), breast carcinoma (MCF-7), and malignant glioma (U-251) were used to demonstrate radiosensitization. Cervical carcinoma (HeLa-S3) and colon carcinoma (HT-29) cells which are not known to contain EM-binding protein were also employed. Cell survival was assayed by the colony forming ability of single plated cells in culture to obtain dose-survival curves.. Pretreatment of DU-145, MCF-7, and U-251 cells to a nontoxic concentration (5 microM) of EM for more than one cell cycle time, substantially enhanced the radiation-induced cytotoxicity. The sensitizer enhancement ratio of these cells ranged from 1.35-1.52. The magnitude of the enhancement was dependent on the drug concentration and exposure time. The rate of cell accumulation in G2/M phase, as determined by flow cytometry, increased with longer treatment time in the cell lines which showed radiosensitization. Other antimicrotubule agents such as taxol and vinblastine caused minimal or no radiosensitization at nontoxic concentrations.. The data provide a radiobiological basis for using EM as a novel radiation enhancer, with the property of tissue selectivity.

Topics: Breast Neoplasms; Cell Cycle; Cell Survival; Colonic Neoplasms; Combined Modality Therapy; Estramustine; Female; Flow Cytometry; Glioma; HeLa Cells; Humans; Male; Microtubules; Neoplasms; Paclitaxel; Prostatic Neoplasms; Radiation-Sensitizing Agents; Tumor Cells, Cultured; Vinblastine

Topics: Administration, Oral; Antibodies, Monoclonal; Chlorambucil; Estradiol; Estramustine; Humans; Neoplasms; Prednimustine; Receptors, Cell Surface

Thirty-five patients with advanced cancers were treated with estramustine phosphate tablets (Estracyt). Doses ranged between 420 mg and 700 mg daily. One partial response was documented in a hormone resistant prostatic cancer patient. Four minor responses (less than 50% responses, or less than one month more than 50% response) were obtained; one in a hormone resistant prostatic cancer, two in metastatic colorectal cancers; and another in a malignant melanoma. Toxicity phenomena included nausea (9/35 - 25%), water retention (4/35 - 11.5%) and mild elevation of alkaline phosphatase (2/35 - 6%). Other toxicity effects were vaginal bleeding in two women, acne in one woman and mild pruritus in another patient. Myelosuppression and immune suppression were not significantly detected.

Topics: Adult; Aged; Colonic Neoplasms; Drug Evaluation; Drug Resistance; Estramustine; Female; Humans; Male; Melanoma; Middle Aged; Neoplasms; Nitrogen Mustard Compounds; Prostatic Neoplasms; Rectal Neoplasms

Topics: Altretamine; Antineoplastic Agents; Cisplatin; Estramustine; Ethyl Chloride; Humans; Neoplasms; Streptozocin; Tamoxifen

Estracyt, a conjugate of estradiol-17beta (E2) and a nitrogen mustard, is a compound which recently has been found to be of value in the treatment of cancer of the prostate. The present study concerned itself with the fate of labeled Estracyt administered 1) either as a mixture of 3H-Estracyt, labeled in the estrogen moiety, and 14C-E2 or 2) as doubly labeled Estracyt with 3H in the E2 and 14C in the carbamate part. These studies were performed in the human and baboon, with biliary excretion studies being performed in the latter. In the human studies with singly labeled Estracyt, it was shown that about 10-15% of the compound is hydrolyzed in such a fashion as to yield E2, which is then metabolized and conjugated similarly to the 14C-labeled E2; and that the excretory pattern in the urine of the released E2, including the CCD pattern, did not differ materially from that of the 14C-E2, though it was excreted at about 1/3 the rate of the 14C-E2. The remainder of the injected Estracyt was not accounted for. No intact Estracyt was found in the urine. When doubly labeled Estracyt was administered to human subjects, it was shown that the excretion of the 14C (carbamate moiety) was much lower than that of the 3H (E2 moiety), indicating that hydrolysis of the molecule did, in fact, take place, but that the excretion of the 14C, as well as the rest of Estracyt, must follow a route other than the urine. The most likely route is the biliary excretion of either intact Estracyt and/or its metabolites and conjugates without any significant enterohepatic circulation, with the bulk ultimately being excreted in the stools. The studies in the baboon mirrored those in the human. We were able, however, to demonstrate substantial excretion of singly and doubly labeled Estracyt in the bile, indicating that this may be the major route by which the compound is excreted in the baboon and, by analogy, in the human.

Topics: Administration, Oral; Aged; Animals; Estramustine; Female; Haplorhini; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasms; Nitrogen Mustard Compounds; Papio; Species Specificity; Time Factors