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Biomedical subjects

G R Hudes

Publications and source records attributed to G R Hudes.

At least 19 recordsLinked to original sources
PubMed2000

Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies.

Perillyl alcohol (POH) is a monoterpene with anticarcinogenic and antitumor activity in murine tumor models. Putative mechanisms of action include activation of the transforming growth factor beta pathway and/or inhibition of p21ras signaling, leading to differentiation or apoptosis. In this Phase I trial, 17 patients took POH p.o. three times daily for 14 days of each 28-day cycle. The starting dose of POH was 1600 mg/m2/dose, with escalations to 2100 and 2800 mg/m2/dose in subsequent cohorts. Chronic nausea and fatigue were dose-limiting toxic effects at 2800 mg/m2. Grade 1-2 hypokalemia was common at 2100 and 2800 mg/m2. Although POH could not be detected in plasma, two of its metabolites, dihydroperillic acid (DHPA) and perillic acid (PA), were measured in plasma and urine on days 1 and 15 after the first and last doses of POH, respectively. Both area under the concentration versus time curve and peak plasma concentration (Cmax) values increased with dose and exhibited high intersubject variability. Day 15 DHPA Cmax values ranged from a mean +/- SD of 22.6+/-12 microM at 1600 mg/m2/dose to 42.4+/-15.24 microM at 2800 mg/m2/dose. Corresponding mean +/- SD Cmax values for PA were 433.2+/-245.8 and 774.1+/-439.6 microM. One patient treated at the 2800 mg/m2/dose had markedly prolonged plasma levels of both PA and DHPA and developed grade 3 mucositis. POH treatment did not consistently alter the expression of p21ras, rap1, or rhoA in peripheral blood mononuclear cells obtained from patients treated at the highest dose level. The metabolites PA and DHPA did not change expression or isoprenylation of p21ras in MCF-7 breast or DU145 prostate carcinoma cells at concentrations that exceeded those achieved in patient plasma after POH treatment. We conclude that POH at 1600-2100 mg/m2 p.o. three times daily is well tolerated on a 14-day on/14-day off dosing schedule. Inhibition of p21ras function in humans is not likely to occur after POH administration at safe doses of the present oral formulation.

Administration, Oral↗
PubMed1999

A phase II study of 5-fluorouracil, leucovorin, and interferon-alpha in the treatment of patients with metastatic or recurrent gastric carcinoma: an Eastern Cooperative Oncology Group study (E5292).

BACKGROUND: Chemotherapy has a limited impact on adenocarcinoma of the stomach. Although biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) and interferon-alpha (IFN-alpha) has improved the outcomes of patients with metastatic colorectal carcinoma compared with 5-FU alone, this approach has not been extensively evaluated in the treatment of advanced gastric carcinoma. METHODS: Twenty-seven patients with bidimensionally measurable, metastatic gastric carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 received the combination of IFN-alpha (5 million U/m2 administered subcutaneously daily on Days 1-7), LV (500 mg/m2 administered intravenously over 30 minutes immediately after IFN-alpha on Days 2-6), and 5-FU (370 mg/m2 given as an intravenous bolus 60 minutes after LV on Days 2-6), with treatment repeated every 4 weeks. Oral cryotherapy was administered routinely before each dose of 5-FU to reduce the incidence of severe stomatitis. RESULTS: The median age of the patients was 58 years (range, 20-76), and 22 patients had residual, unresectable primary lesions. The median number of cycles received was 3 (range, 1-11). Of 24 patients who received at least 2 cycles of treatment, 15 (62.5%) did not require dose reduction for toxicity during the initial 2 cycles. The predominant toxicities were gastrointestinal: diarrhea and stomatitis of Grade 3-4 occurred in 28.6% and 35.7% of patients, respectively. Other severe (Grade 3-4) toxicities were granulocytopenia (which occurred in 21.4% of patients) and fatigue (in 10.7%). Fever and flu-like symptoms were common but usually mild. Of 24 patients who were evaluable for response, 3 had partial responses (PR) of 16, 23, and 33 weeks' duration, respectively, for a response rate of 12.5% (95% confidence interval = 2.7-32.4%). Two additional patients had reductions in tumor size sufficient for PR, but scans to document the minimum required response duration of 4 weeks were not obtained before progressive disease occurred. The median progression-free and overall survivals were 2.5 and 7.8 months, respectively. CONCLUSIONS: Although this regimen can be administered safely with appropriate supportive care to patients with good performance status, it has limited therapeutic activity in patients with advanced gastric carcinoma.

Adult↗
PubMed1999

Preliminary results of a bone marrow magnetic resonance imaging protocol for patients with high-risk prostate cancer.

OBJECTIVES: To compare the accuracy of a bone marrow magnetic resonance imaging (MRI) protocol in patients at high risk of metastatic disease with radioisotopic bone scans, the standard method for detection of bony metastases in patients with prostate cancer. METHODS: The study group consisted of 19 men with prostate cancer who underwent a bone marrow MRI between November 1993 and February 1996. This protocol images the marrow of the thoracolumbar spine, sacrum, pelvis, and femurs. Indications for MRI included an equivocal bone scan and/or staging of locally advanced or recurrent disease. The findings on MRI and bone scan were compared and the results correlated with the subsequent clinical patient outcome. RESULTS: The bone marrow MRI protocol detected metastatic disease in 1 (7%) of 13 patients with negative bone scans. Four patients had an indeterminate bone scan: 2 had true-positive MRIs, 1 a true-negative MRI, and 1 a false-positive MRI on the basis of subsequent clinical follow-up. Two patients with positive bone scans had true-positive MRIs. CONCLUSIONS: Although not recommended for routine staging, MRI was useful in this study for clarifying an equivocal bone scan. The bone marrow MRI protocol images a high yield volume of the bony skeleton and is fast and economical compared with obtaining many focused MRI scans of these areas separately. These preliminary data suggest that further investigation of its clinical utility for staging locally advanced or recurrent disease is justified.

Adenocarcinoma↗
PubMed1998

Cloning and sequencing of human betaIII-tubulin cDNA: induction of betaIII isotype in human prostate carcinoma cells by acute exposure to antimicrotubule agents.

Antimicrotubule drugs are used as chemotherapeutic agents due to their effects on essential cellular functions such as mitosis, organelle transport and maintenance of cell shape. When used in combination, paclitaxel with estramustine or vinblastine has demonstrated activity against hormone refractory prostate cancer. To understand the mechanism of resistance that develops in patients as a result of antimicrotubule drug therapy, we exposed human prostate carcinoma cells to IC20 and IC40 doses of estramustine, paclitaxel or vinblastine for 48 h and examined the beta-tubulin (the cellular target) isotype composition. The results revealed an increase in the betaIII-tubulin isotype as a result of drug treatment both at protein and message levels. In addition, examination of human brain cell lines with different intrinsic levels of betaIII showed that cell lines with higher betaIII levels were more resistant to paclitaxel. These results are in agreement with our previous findings in human prostate carcinoma cell lines that were made resistant to estramustine or paclitaxel and suggest an important function for betaIII in antimicrotubule drug resistance. Also, the complete coding sequence of human betaIII tubulin reported here will provide molecular tools for future investigations.

Amino Acid Sequence↗
PubMed1998

Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells.

To investigate the role of beta-tubulin isotype composition in resistance to paclitaxel, an anti-microtubule agent, human prostate carcinoma (DU-145) cells were intermittently exposed to increasing concentrations of paclitaxel. Cells that were selected and maintained at 10 nM paclitaxel (Pac-10) were fivefold resistant to the drug. Pac-10 cells accumulated radiolabelled paclitaxel to the same extent as DU-145 cells and were negative for MDR-1. Analysis of Pac-10 and DU-145 cells by flow cytometry showed similar cell cycle patterns. Immunofluorescent staining revealed an overall increase of alpha- and beta-tubulin levels in Pac-10 cells compared with DU-145 cells. Examination of beta-tubulin isotype composition revealed a significant increase in betaIII isotype in the resistant cells, both by immunofluorescence and by western blot analysis. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the isotypes confirmed the increase observed for the betaIII by exhibiting ninefold higher betaIII mRNA levels and also showed fivefold increase of the betaIVa transcript. In addition, analysis of paclitaxel-resistant cells that were selected at increasing levels of the drug (Pac 2, 4, 6, 8 and 10) exhibited a positive correlation between increasing betaIII levels and increasing resistance to paclitaxel. Increased expression of specific beta-tubulin isotypes and subsequent incorporation into microtubules may alter cellular microtubule dynamics, providing a defence against the anti-microtubule effects of paclitaxel and other tubulin-binding drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Cisplatin-based chemotherapy for testicular cancer in a patient with spinal muscular atrophy: a case report.

Metastatic germ-cell tumors of the testis are highly curable with cisplatin-based chemotherapy. Although cisplatin-based chemotherapy is generally well tolerated and rarely causes severe neurotoxicity, there is little information to guide the treatment of patients with neuromuscular disorders. The authors report the successful treatment of a patient with testicular cancer and spinal muscular atrophy, an inherited degenerative neuromuscular disease.

Adult↗
PubMed1997

Immunohistochemical analysis of beta-tubulin isotypes in human prostate carcinoma and benign prostatic hypertrophy.

BACKGROUND: beta-tubulin, the intracellular target of several antimicrotubule agents, is encoded by at least six genes and exists as multiple isotypes with tissue-specific expression. Previous in vitro studies indicated that tubulin isotype composition may affect polymerization properties, dynamics, and sensitivity to drugs. METHODS: To investigate the isotype composition of beta-tubulin in human prostate, tissues were collected from 26 patients after radical prostatectomy and sections were stained with isotype-specific antibodies. RESULTS: beta IV tubulin is the predominant isotype in benign prostatic hyperplasia (BPH) and adenocarcinoma, showing significantly stronger immunohistochemical expression than beta II and beta III, particularly in Gleason's grade 3 and 4 cancers. Staining for the beta II isotype was invariably weak and often absent in BPH and normal glands. There was a marked increase in beta II isotype stain from BPH to cancer in 77% of the patients, suggesting that the expression of this isotype is related to malignant status. CONCLUSIONS: The beta II tubulin isotype is a potential marker for prostate adenocarcinoma. The possibility that tumor beta-tubulin isotype composition may effect the response to antimicrotubule drug therapy in prostate cancer and other tumors merit investigation.

Carcinoma↗
PubMed1997

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside (MMPR), and leucovorin in patients with advanced cancer.

The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m2 day 1, followed 24 h later by MMPR 150 mg/m2 as an iv bolus, and the initiation of a 24-hour infusion of 5-FU along with leucovorin 50 mg/m2. This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m2. Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m2. There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.

Adult↗
PubMed1997

Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer.

PURPOSE: To evaluate the antitumor activity of 96-hour paclitaxel and daily oral estramustine phosphate (EMP) in patients with metastatic hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Thirty-four patients with adenocarcinoma of the prostate that progressed after one or more hormonal therapies and a trial of antiandrogen withdrawal were enrolled onto this phase II trial. Patients received paclitaxel 120 mg/m2 by 96-hour intravenous (i.v.) infusion on days 1 through 4 of each 21-day cycle, together with daily oral EMP 600 mg/m2/d, continuously. RESULTS: Four of nine patients with measurable disease had objective responses (one complete response [CR] and three partial responses [PRs]) in liver (two patients) or nodes (two patients) of 2, 6, 8, and 20 months' duration. Of 25 assessable patients with metastases limited to bone, 14 had a > or = 50% decline in pretreatment prostate-specific antigen (PSA) level sustained for at least 6 weeks and seven had a > or = 80% decline. Overall, 17 of 32 patients (53.1%) with elevated pretreatment PSA levels had a > or = 50% decline of PSA and nine (28.1%) had a > or = 80% decrease. The main toxicities (> or = grade 2) were nausea, fluid retention, and fatigue, which occurred in 33%, 33%, and 24.2% of patients. Median time to progression, based on increasing PSA level and other clinical criteria, was 22.5 weeks. The estimated median overall survival time is 69 weeks. CONCLUSION: The combination of EMP and 96-hour paclitaxel is an active regimen for patients with HRPC. These results further support the therapeutic strategy of combining agents that impair microtubule function by complementary mechanisms.

Adenocarcinoma↗
PubMed1996

Increase of beta(III)- and beta(IVa)-tubulin isotopes in human prostate carcinoma cells as a result of estramustine resistance.

Estramustine (EM), an antimicrotubule agent, is effective against hormone-refractory prostate cancer when used in combination with vinblastine or paclitaxel. To understand the effect of EM on beta-tubulin, a cellular target for this class of drugs, human prostate carcinoma cells (DU-145) were made resistant to EM, and two cell lines were selected at 12- (EM-12) and 15-microMolar (EM-15) concentrations of the drug. These cell lines exhibited 8- to 9-fold resistance to EM and 2- to 4-fold cross-resistance to paclitaxel. Immunofluorescent staining of the cells with beta-tubulin isotype-specific antibodies showed an approximately 6-fold increase in the beta(III)-tubulin levels and moderate increase in overall beta-tubulin levels in EM-resistant cells when compared to DU-145 cells. This increase of beta(III) isotype was confirmed by Western analysis. A reverse transcriptase-PCR assay was also employed using beta-tubulin isotype-specific primers to quantify beta-tubulin isotype RNA. A 4-fold increase in beta(III) and a 3-fold increase in beta(IV alpha) transcript were seen in both EM-resistant cell lines. These results indicate that overexpression of specific beta-tubulin isotypes may play a role in the cellular defense against EM and other antimicrotubule agents.

Antineoplastic Agents↗
PubMed1996

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside.

Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-L-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m2 given on day 1, followed 24 h later by MMPR 150 mg/m2, and escalating doses of 5-FU from 1625 to 2600 mg/m2 by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m2. Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m2, MMPR 150 mg/m2, and 5-FU 2300 mg/m2 by continuous infusion over 24 h.

Adult↗
PubMed1995

Modulation of P-glycoprotein activity by estramustine is limited by binding to plasma proteins.

BACKGROUND: Estramustine previously has been shown to interact with P-glycoprotein and to restore intracellular accumulation of vinblastine and paclitaxel in cells overexpressing this drug transporter. However, the ability of estramustine to potentiate the cytotoxicities of several drugs was less than that expected. To resolve this apparent discordance, the authors examined the effects of serum on the actions of estramustine. METHODS: The cytotoxicities of anticancer drugs with or without estramustine or verapamil toward MCF-7 breast carcinoma cells and a P-glycoprotein-overexpressing subline MCF-7/ADR were determined using the sulforhodamine-binding assay. The extent of intracellular accumulation of [3H]vinblastine and [3H]paclitaxel was determined for each using standard methods, and the binding of radiolabeled drugs to plasma proteins was characterized by equilibrium dialysis. RESULTS: Without serum, the sensitivities of MCF-7/ADR cells to several P-glycoprotein-transported drugs were increased by estramustine and verapamil. Conversely, when the cells were treated with a 10% serum, the cytotoxicities of these drugs were increased by verapamil, but not by estramustine. Without serum, intracellular accumulation of [3H]vinblastine and [3H]paclitaxel by MCF-7/ADR cells was increased markedly by verapamil and estramustine; however, serum suppressed the effects of estramustine much more strongly than those of verapamil. Equilibrium dialysis experiments demonstrated that [3H]estramustine binds to plasma proteins, predominantly albumin, whereas [3H]paclitaxel binds to albumin and alpha 1-acid-glycoprotein, and [3H]vinblastine binds predominantly to alpha 1-acid-glycoprotein. CONCLUSION: Although estramustine can bind to P-glycoprotein, its effectiveness as a reversing agent in vivo likely is limited by binding to plasma proteins.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Phase I study of phosphonacetyl-L-aspartate, 5-fluorouracil, and leucovorin in patients with advanced cancer.

Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 microM suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 microM. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m2 PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m2 admixed with 50 mg/m2 leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m2. Dose modification resulted in a mean dose intensity of 2,300 mg/m2 at both the 2,600- and 2,300-mg/m2 dose levels. The 2,300-mg/m2 dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (Css) of 5-FU in 23 patients. The mean Css increased with dose from 0.738 to 1.03 micrograms/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean Css (1.10 +/- 0.19) than those with grade O or I toxicity (0.835 +/- 0.25, P < 0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU Css values.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Phase II study of topotecan in metastatic hormone-refractory prostate cancer.

Systemic chemotherapy with currently available agents has not improved survival for patients with hormone refractory prostate cancer (HRPC), consequently, the evaluation of new agents is warranted. Topotecan is a specific inhibitor of topoisomerase I with broad antitumor activity in preclinical studies. The purpose of this phase II trial was to determine the objective response rate of topotecan administered as a 30 minute infusion for five consecutive days in men with metastatic HRPC. Thirty-four evaluable patients were treated with topotecan 1.1-1.5 mg/m2 as a 30 minute infusion daily for five days, repeated every three weeks until disease progression or unacceptable toxicity. Response was assessed with a combination of standard solid tumor response criteria and the serum prostate specific antigen (PSA) for patients with bidimensionally measurable disease, and by serial measurements of the PSA in patients with bone only (evaluable) disease. One of 13 patients (7.6%) with measurable soft tissue disease had a PR in nodal sites. Of 21 patients with only osseous metastases, 1 (4.7%) had improvement in bone scan. Six of the 34 evaluable patients (17.6%) had the serum PSA decrease by > or = 50% and 2 (5.8%) had PSA decreases of > or = 75%. Toxicity was chiefly hematologic with 66% of patients experiencing Grade 3 or 4 granulocytopenia. Thirty-nine percent of cycles required a delay to allow for hematologic recovery and ten patients required red cell transfusions. Non-hematologic toxicity, mainly nausea and alopecia, was mild. Topotecan administered at this dose and schedule has limited activity in patients with HRPC. Further trials of topo I inhibition in HRPC should utilize alternative schedules of topotecan (e.g., prolonged infusion) or other camptothecin analogs with more potent topo I inhibitory activity.

Aged↗
PubMed1995

Paclitaxel plus estramustine in metastatic hormone-refractory prostate cancer.

Combination antimicrotubule therapy with estramustine phosphate (EMP) and vinblastine has reproducible activity in metastatic hormone-refractory prostate cancer (HRPC) with an objective response rate of 31%. Although paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 24-hour infusion was inactive in HRPC, 0.5 to 1.0 nmol/L concentrations of paclitaxel combined with EMP exerted synergistic cytotoxicity in DU-145 androgen-independent human prostate cancer cell lines. Based on these results, we treated 24 patients with HRPC using the combination of paclitaxel 120 to 140 mg/m2 by 96-hour intravenous infusion every 3 weeks plus daily oral EMP at 600 mg/m2/d. Of seven patients with measurable soft tissue metastases, three have attained partial responses and a fourth patient is nearing partial response status. Of 16 patients with bone-only disease evaluated by change in serum prostate-specific antigen levels, 11 patients (68.8%) have had decreases of > or = 50% from pretreatment baseline. The prostate-specific antigen decrease has exceeded 80% in six of 16 (37.5%) patients. For all 23 evaluable patients, the prostate-specific antigen has decreased by > or = 50% in 15 (65.2%) and by > or = 80% in eight (34.7%). Grade 4 leukopenia occurred in one of 21 patients treated at the paclitaxel dose of 120 mg/m2/96 hr and one of three patients treated at 140 mg/m2/96 hr. The incidence of nausea (50%) and peripheral edema (37.5%) was similar to that associated with single-agent EMP. These results demonstrate that 96-hour paclitaxel plus EMP is active in HRPC and provide further evidence that the rational combination of antimicrotubule agents leads to synergistic antitumor activity in HRPC.

Adenocarcinoma↗
PubMed1995

Phase I study of paclitaxel and estramustine: preliminary activity in hormone-refractory prostate cancer.

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.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

P-glycoprotein binding and modulation of the multidrug-resistant phenotype by estramustine.

BACKGROUND: Previous preclinical studies of combinations of estramustine and vinblastine or paclitaxel (Taxol) have shown that it is possible to achieve a greater than additive cytotoxicity with these antimicrotubule drug combinations. Phase II studies in hormone-refractory prostate cancer have demonstrated clinical antitumor activity of sufficient magnitude to stimulate further laboratory and clinical studies of these drugs combinations. PURPOSE: Our purpose was to characterize the interactions of estramustine with P-glycoprotein and to determine its effects. METHODS: Standard laboratory techniques were used to study the effects of estramustine on intracellular drug concentrations, cytotoxicity, and induction of messenger RNA (mRNA) for the MDR1 (also known as PGY1) gene. Using a photoaffinity analogue of estramustine 17-0-[[2-[3-(4-azido-3-[125I]-iodophenyl) propionamido]ethyl]-carbamyl]estradiol-3-N-bis(2-chloroethyl)ca rba mate ([125I]AIPP-estramustine), binding to the membrane proteins of human ovarian (SKOV3) and their multidrug-resistant counterpart SKVLB1 cells was studied. Southern-blot analysis was performed on DNA extracted from human prostate carcinoma wild-type DU145, estramustine-resistant cell line (E4), and SKVLB1 cells. RESULTS: Membrane fractions from SKOV3 and SKVLB1 cells were analyzed for proteins that could be photoaffinity labeled with [125I]AIPP-estramustine. Competitive inhibition of this binding was achieved with excess concentrations of (in order of efficacy) estramustine, vinblastine, verapamil, progesterone, and to a lesser degree, by paclitaxel but not with estramustine phosphate, estradiol, and estriol. SKVLB1 cells accumulated much less [3H]vinblastine and [3H]paclitaxel than did SKOV3 cells. Estramustine caused a concentration-dependent enhancement of drug accumulation in the SKVLB1 cells to a maximum of approximately 12-fold. No effect of estramustine was apparent for the wild-type SKOV3 cells. In comparison with verapamil, estramustine was less effective as a modulator; however estramustine demonstrated good chemosensitizing activity in combination with actinomycin D and vinblastine. Neither short-term, low-dose no longer-term, higher concentration were found to produce measurable transcript (mRNA for the MDR1 gene levels. Such data suggest that, at least levels. Such data suggest that, at least for two distinct human cell line (SKOV3 and DU145), estramustine does not induce the overexpression of the MDR1 gene. CONCLUSION: It is apparent from the P-glycoprotein data that estramustine interacts with this efflux pump, altering intracellular drug accumulation. Overall, the nonempiric basis for including estramustine in clinical protocols that contain other multidrug-resistant drugs is strengthened by the present data.

ATP Binding Cassette Transporter, Subfamily B, Mem↗