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Biomedical subjects

M W DeGregorio

Publications and source records attributed to M W DeGregorio.

At least 37 records · Page 2Linked to original sources
PubMed1993

Tamoxifen resistance in breast cancer.

Tamoxifen (TAM) resistance is the underlying cause of treatment failure in many breast cancer patients receiving TAM. The mechanism(s) involved in TAM resistance are poorly understood. A variety of mechanisms have been proposed but only limited evidence exists to substantiate them. Studies have now shown that in many patients TAM resistance is not related to the down regulation or loss of estrogen receptors (ER). Variant ER have been identified, but their significance clinically remains to be proven. Since breast cancer cells secrete several estrogen-regulated growth factors and growth inhibitors that may have autocrine or paracrine activity, altered growth factor production is another possible mechanism for TAM resistance. Tissue-specific transcription activating factors that may alter how the signal induced by TAM binding to the receptor is interpreted by the cell also require further investigation. An increase in antiestrogen binding sites (AEBS), which could effectively partition TAM and reduce its concentration at the ER has also been proposed as a potential mechanism. Pharmacologic mechanisms, such as a shift in metabolism toward the accumulation of estrogenic metabolites, are supported by recent data demonstrating metabolite E and bisphenol in tumors from TAM-resistant patients. Furthermore, a decrease in tumor TAM accumulation and an altered metabolite profile have been reported in TAM-resistant breast tumors grown in nude mice. These and other studies suggest that TAM resistance may be multifactorial in nature, but definitive identification of mechanisms that are operative in clinical TAM resistance requires further study.

Animals↗
PubMed1993

A breast cancer clone selected by tamoxifen has increased growth rate and reduced sensitivity to doxorubicin.

The in vivo growth rate and the chemosensitivity patterns of a cell clone selected by tamoxifen from the estrogen receptor-negative human breast cancer cell line MDA-MB-231 was studied in the nude mouse model and with flow cytometry. To investigate the growth rate of the wild-type and clone cells in vivo, the cells were inoculated into the opposite flanks of 5 male nude mice. Drug sensitivity to doxorubicin (10 ng/mL), vinblastine (1 ng/mL), and paclitaxel (1 ng/mL) was examined in wild-type/clone cell mixture using flow cytometry. Northern blot technique was used to study the expression of mdr-1 messenger RNA in both the wild-type and the clone cells. The tumors derived from the clone and wild-type cells were, following a 3-week growth period, 260.2 +/- 78.8 mm2 vs. 68.3 +/- 50.8 mm2 in size, respectively (P < 0.001). Following a 28-day continuous exposure, doxorubicin was selectively, toxic to the wild-type cells, while having no apparent effect on the clone population. However, paclitaxel- and vinblastine-treated wild-type/clone cell mixtures did not exhibit a differential cytotoxic effect on either cell population. It was concluded that the clone selected by tamoxifen shows an aggressive growth rate in vivo and an altered chemosensitivity pattern to doxorubicin in vitro.

Animals↗
PubMed1993

Toremifene enhances cell cycle block and growth inhibition by vinblastine in multidrug resistant human breast cancer cells.

The clinical study of compounds that modulate multidrug resistance has been hindered by both the toxicities of these agents and the inability to monitor their effectiveness at the level of the tumor cell. Previously, toremifene has been shown to be well tolerated clinically and to sensitize multidrug resistant cells to the effects of cytotoxic chemotherapeutic agents. The chemosensitizing properties of toremifene in estrogen receptor negative, multidrug resistant MDA-MB-A1 human breast cancer cells were studied using flow cytometric analysis and growth inhibition assays. Cell cycle kinetics of MDA-MB-A1 cells were not significantly affected by treatment with either toremifene, N-desmethyltoremifene, Toremifene IV or vinblastine alone, as the majority of cells remained in G0/G1. However, preincubation with toremifene or one of its metabolites for 72 hours followed by treatment for one hour with vinblastine caused a marked shift of cells to G2/M, as cells appeared to be blocked in that phase of the cell cycle. This result was nearly identical to the effect of vinblastine alone on vinblastine-sensitive MDA-MB-231 breast cancer cells and can be interpreted as a "resensitization" by toremifene of MDA-MB-A1 cells to vinblastine. This chemosensitizing effect of toremifene was accompanied by an enhanced inhibition of cell growth by vinblastine. The chemosensitizing effects of toremifene or one of its metabolites in combination with cytotoxic chemotherapy can be effectively monitored by flow cytometry, an easily accessible technique.

Breast Neoplasms↗
PubMed1992

Monitoring the chemosensitizing effects of toremifene with flow cytometry in estrogen receptor negative multidrug resistant human breast cancer cells.

The clinical study of compounds that modulate multidrug resistance in cancer cells has been hindered by both the toxicities of these agents and the inability to monitor their effectiveness at a cellular level. The non-steroidal triphenylethylene toremifene is well tolerated clinically and can sensitize multidrug resistant cells to the effects of doxorubicin in vitro. The chemosensitizing properties of toremifene in estrogen receptor negative, multidrug resistant MDA-A1 human breast cancer cells were studied using flow cytometric analysis. Cell cycle kinetics of MDA-A1 cells were not significantly affected by treatment with either toremifene or doxorubicin alone, as the majority of cells remained in G0/G1. However, preincubation with toremifene for 70 hours followed by treatment with doxorubicin caused a marked shift of cells to G2, as cells appeared to be blocked in that phase of the cell cycle. This result was nearly identical to the effect of doxorubicin alone on doxorubicin-sensitive MDA-MB-231 breast cancer cells and can be interpreted as a "resensitization" by toremifene of MDA-A1 cells to doxorubicin. This chemosensitizing effect of toremifene was accompanied by an enhanced accumulation of doxorubicin in MDA-A1 cells (+110% after 70 hours pre-incubation with toremifene), and by a depression in protein kinase C activity in MDA-A1 cells that was maximal following 70 hours incubation with toremifene. Flow cytometry is a widely available technique that might be applied clinically to monitor at the cellular level the chemosensitizing effects of toremifene and other modulators of multidrug resistance.

Breast Neoplasms↗
PubMed1992

Tamoxifen and the isomers of 4-hydroxytamoxifen in tamoxifen-resistant tumors from breast cancer patients.

PURPOSE: The antiestrogen tamoxifen is effective in therapy for breast cancer. However, its use is limited by the eventual development of acquired tamoxifen resistance in many patients. The mechanisms responsible for tamoxifen resistance remain unknown; loss of estrogen receptor (ER), selection of hormone-independent breast cancer clones, or alterations in serum tamoxifen levels after long-term use do not explain acquired resistance in most patients. Using an experimental model in which human breast cancer cells develop resistance in athymic mice treated with tamoxifen, we have recently shown that acquired resistance is associated with markedly reduced cellular concentrations of tamoxifen and by isomerization of the trans-4-hydroxy metabolite to the less potent cis isomer. MATERIALS AND METHODS: Using a sensitive high-performance liquid chromatography (HPLC) assay, we have now measured levels of tamoxifen and its major metabolites in a series of 14 tumors from patients treated with tamoxifen. The duration of therapy ranged from 1 month to 6 years. RESULTS: Tumor tamoxifen levels varied over a wide range. Low concentrations were observed in tumors from eight patients, all demonstrating progressive disease at the time of biopsy after a minimum duration of treatment of 6 months. Six tumors had moderate to high tamoxifen levels, two from patients responding to tamoxifen, one from a patient with stable disease, and three from patients with disease progression. Both the cis and trans isomers of the potent antiestrogenic metabolite 4-hydroxy-tamoxifen were detected in 11 tumors. Six tumors had high ratios of the cis to trans isomer (1.10:2.06), all from patients not responding to tamoxifen. The five tumors with low cis:trans ratios included the two tumors from responding patients and three from patients with progression. All but one of the 11 nonresponding patients had either a low tumor tamoxifen level, a high cis:trans ratio, or both. CONCLUSION: This study clearly demonstrates a wide range of tumor tamoxifen levels and accumulation of the less antiestrogenic cis isomer of 4-hydroxytamoxifen in some patients on tamoxifen therapy. Additional study is necessary to determine if these metabolic profiles are related to the development of tamoxifen resistance.

Adult↗
PubMed1992

Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors.

PURPOSE: We have shown previously that acquired tamoxifen resistance in an in vivo experimental model is associated with reduced tamoxifen accumulation, isomerization of trans-4-hydroxytamoxifen, and tamoxifen-stimulated tumor growth. The purpose of this study is to isolate and verify the presence of estrogenic tamoxifen metabolites in human breast tumors using high-performance liquid chromatography (HPLC) and mass-spectrometry (MS) techniques. PATIENTS AND METHODS: In the present study, we used HPLC and MS to identify the presence of estrogenic metabolites in tumor samples excised from athymic nude mice and in human breast tumors isolated from patients receiving adjuvant tamoxifen therapy. RESULTS: We identified the presence of metabolite E, a known estrogenic metabolite of tamoxifen, in tamoxifen-resistant MCF-7 human breast tumors implanted in athymic nude mice, as well as in tumors from patients with clinical resistance. Additionally, we separated another estrogenic metabolite, bisphenol, by HPLC, and this was also tentatively confirmed by MS analysis. CONCLUSION: These data suggest that cellular tamoxifen metabolism to estrogenic metabolites may in part contribute to stimulating the growth of hormone-responsive breast tumors following prolonged exposure to tamoxifen. Further evaluation of the relationship between cellular metabolism and acquired tamoxifen resistance is warranted.

Animals↗
PubMed1990

Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer.

A multicenter phase I pharmacokinetic study of a new triphenylethylene antiestrogen, toremifene, was examined in 70 patients with advanced breast cancer. Patients were randomized to receive single daily oral doses of either 10, 20, 40, 60, 200, or 400 mg for 8 weeks. Plasma toremifene and its major metabolites. N-desmethyltoremifene and 4-hydroxytoremifene, were determined weekly during therapy and at 0, 7, 14, and 21 days after the discontinuation of therapy. The time to reach steady-state plasma concentrations was between 1 and 5 weeks, with steady-state being achieved earlier (1-2 weeks) at daily doses of 200 and 400 mg. The time to peak concentration following oral doses of toremifene ranged from 1.5 to 4.5 h. The terminal half-life of elimination was 5.0, 6.0, and 5.0 days for toremifene, desmethyltoremifene, and 4-hydroxytoremifene, respectively. Plasma concentrations of 4-hydroxytoremifene were detectable only at high doses (200 and 400 mg/day) of toremifene. The results of this phase I pharmacokinetic study show that toremifene has metabolic and kinetic patterns that are similar to those previously reported with tamoxifen.

Administration, Oral↗
PubMed1990

Phase I study of the tolerance and pharmacokinetics of toremifene in patients with cancer.

Toremifene is a triphenylethylene derivative structurally and pharmacologically similar to tamoxifen. This Phase I trial assessed the safety, pharmacokinetics, anti-estrogenic, and estrogenic effects of toremifene at six dose levels (10, 20, 40, 60, 200, and 400 mg/day). The most common side-effects associated with therapy included gastrointestinal (nausea/vomiting 43%), anti-estrogenic (hot flashes 29%), and CNS (dizziness/vertigo 12%). Three patients with bone metastases from breast cancer developed hypercalcemia. At doses greater than or equal to 40 mg/day a decline in LH and FSH occurred which was not statistically significant. At all doses tested SHBG rose during therapy. A dose dependent estrogenic blockade was seen on the vaginal epithelium following challenge with transdermal estradiol. Steady-state concentrations of toremifene were reached within 4 weeks, and at doses greater than or equal to 60 mg/day ranged from 879-3445 ng/ml. The half-life was found to be 5 days, and at three weeks following discontinuation of treatment concentrations greater than 24 ng/ml were detected. The N-desmethyl and 4-hydroxy metabolites achieved steady state levels within 4 weeks and had half-lives of 6 and 5 days respectively. Partial responses were seen in 4 patients, 3 with breast cancer treated at 200 mg/day and 1 with endometrial cancer treated at 400 mg/day.

Adult↗
PubMed1990

Cisplatin rescue therapy: experience with sodium thiosulfate, WR2721, and diethyldithiocarbamate.

Cisplatin has a steep dose response curve for both antitumor and adverse effects. Therapeutic strategies aimed at reducing toxicity and allowing dose escalation of intravenous cisplatin, such as administration in hypertonic saline and pharmacokinetically based dosing schedules, have been partially successful in reducing nephrotoxicity and bone marrow suppression. However, new dose-limiting toxicities consisting of peripheral neuropathy and ototoxicity have emerged, which continue to restrict potential use of high dose cisplatin therapy. Intraperitoneal administration of high dose cisplatin also offers the potential of markedly increased local drug exposure if systemic toxicity can be avoided. Proposed chemoprotective agents, including sodium thiosulfate, WR2721, and diethyldithiocarbamate (DDTC) are being extensively examined as "rescue agents" for either regional or systemic administration of cisplatin. Although each agent offers unique advantages to be considered in developing successful rescue therapy, many questions remain regarding molecular and pharmacokinetic interactions with cisplatin, appropriate dosing schedules, and effects on antineoplastic activity. We present a review of current investigations of chemoprotectors for prevention of cisplatin-related toxicities.

Amifostine↗
PubMed1989

Pharmacokinetics of cisplatin in patients receiving interleukin-2-containing treatment regimens.

Plasma cisplatin pharmacokinetics were determined in 6 patients enrolled in a phase I trial of combined high-dose cisplatin and Interleukin-2 (IL-2) therapy. Cisplatin (100 mg/m2) was given in 3% saline as a 3-h infusion on days 1 and 8 of each 28-day cycle; IL-2(2-4 x 10(6) units/m2) was given as an i.v. bolus on days 15-19 in a dose escalation trial. Peak total and ultrafiltrate plasma platinum concentrations were 1.15 and 0.172 micrograms/ml for cycle 1 and 1.2 and 0.124 micrograms/ml for cycle 3, respectively. The AUCs for total and ultrafiltrate plasma platinum were 7.33 and 0.965 micrograms/ml per hour for cycle 1 and 8.48 and 0.924 micrograms/ml per hour for cycle 3, respectively. Total body clearances for total and ultrafiltrate platinum were 0.051 and 0.525 ml/h for cycle 1 and 0.042 and 0.443 ml/h for cycle 3, respectively. These data demonstrate no significant effects of IL-2 on the plasma pharmacokinetics of cisplatin in the dose schedule given and support the feasibility of this combined modality therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Tumor and serum tamoxifen concentrations in the athymic nude mouse.

The athymic nude mouse has been used as an in vivo model for pharmacologic studies of the antiestrogen, tamoxifen. Serum and tumor tamoxifen and metabolite concentrations were examined during and after 100 and 1000 micrograms/day doses injected s.c. Tamoxifen and tamoxifen metabolites were quantitated by high-performance liquid chromatography. Tamoxifen was detected in tumors after a dose of 100 micrograms/day, although serum concentrations were not detected. At a dose of 1000 micrograms/day, tumor tamoxifen and its active metabolites were detected in high concentrations ranging up to greater than 6 mmol/g tissue. Serum tamoxifen metabolites were not detected at either dose. In summary, high doses of tamoxifen were required in the nude mouse to obtain clinically relevant serum concentrations, and significant tumor levels were achieved at doses that resulted in undetectable serum levels. The relationship between serum tamoxifen concentrations, tumor tamoxifen levels, and the biologic activity of the drug requires further study.

Animals↗
PubMed1989

High-dose cisplatin with diethyldithiocarbamate (DDTC) rescue therapy: preliminary pharmacologic observations.

Diethyldithiocarbamate (DDTC), a chelating agent that is a major metabolite of disulfuram, has been proposed as a potential rescue agent to reduce toxicity following high-dose cisplatin (HDCP) therapy. In the present study, we examined the pharmacologic interaction of HDCP and DDTC given as rescue therapy. Total plasma platinum and ultrafiltrate platinum pharmacokinetics and DDTC levels were determined in six patients with advanced malignancies who received a total of 11 cycles of HDCP with DDTC rescue. HDCP therapy (200 mg/m2 per cycle) consisted of 100 mg/m2 reconstituted in 250 cc 3% saline and infused over 3 h on days 1 and 8 of each 28-day cycle. DDTC rescue at a dose of 4 gm/m2 was given by an i.v. infusion (duration 1.5-3.5 h), beginning 45 min after the completion of cisplatin infusion. Peak total and ultrafiltrate levels and cisplatin pharmacokinetics in this study were indistinguishable from those of previous studies using the same HDCP regimen without DDTC rescue. Ultrafiltrate or unbound plasma platinum was less than 10% of total plasma platinum concentrations and demonstrated a biphasic pattern of elimination. Levels of DDTC predicted to be chemoprotective (greater than 400 microM) were achieved with the dose and schedule used in this study. These data demonstrate that DDTC can be targeted to protective plasma concentrations without significantly altering plasma cisplatin pharmacokinetics and support the potential usefulness of DDTC as a rescue agent following HDCP therapy.

Cisplatin↗
PubMed1989

Toremifene: pharmacologic and pharmacokinetic basis of reversing multidrug resistance.

Triphenylethylene compounds, such as tamoxifen, have shown chemosensitizing activity independent of estrogen receptor status in doxorubicin-resistant cells. We examined the chemosensitizing activity of a new triphenylethylene, toremifene, and its major metabolites in a doxorubicin-resistant human breast cell line, MCF-7/DOX. In addition, we examined the chemosensitizing activity of unbound plasma toremifene and its metabolites isolated from patients treated with toremifene doses of 20 to 400 mg/d. MCF-7/DOX cells were exposed to ultrafiltrate plasma specimens in the absence and presence of doxorubicin. These latter studies were single-blinded. Toremifene and its major metabolites were capable of sensitizing multidrug-resistant cells to doxorubicin. The degree of chemosensitizing activity in vitro correlated with the plasma concentrations of toremifene and its metabolites (P less than .05). Plasma samples isolated from patients receiving high-dose toremifene (400 mg/d) had the greatest chemosensitizing activity. We present evidence that toremifene and its metabolites can sensitize resistant MCF-7/DOX cells to doxorubicin, that this effect is concentration-dependent, and that sensitizing activity can be detected at clinically achieved concentrations.

Blood↗
PubMed1988

Evolution of high-dose cisplatin.

High-dose cisplatin therapy, defined as 200 mg/m2/course, is currently undergoing extensive clinical trials in a variety of solid tumors. The reduction of the incidence and severity of cisplatin-induced nephrotoxicity has led to clinical trials of higher doses of cisplatin. By maintaining nephrotoxicity to acceptable levels, dose response relationships have shown increased efficacy of cisplatin therapy. However, new dose-limiting toxicities, primarily severe neurotoxicity and myelosuppression, have prevented further dosing increases. The following review will trace the evolution and the current status of high-dose cisplatin therapy. In addition, a summary of the dose-limiting non-renal toxicities and their relationship to pharmacokinetics and dosing schedules will be discussed.

Cisplatin↗
PubMed1988

Estrogen priming in advanced breast cancer.

The successful treatment of advanced breast cancer has reached a plateau in recent years. Estrogen priming is a new combination therapy involving estrogens, antiestrogens, and chemotherapy that may result in the improvement of treatment responses. This investigational therapy is designed to synchronize cell cycles with estrogens and antiestrogens in order to enhance the activity of cell cycle-specific anticancer drugs. The pharmacological manipulation of cell growth coupled with appropriate antineoplastic agents could result in a new treatment approach for advanced breast cancer. The rationale and current status of estrogen priming are reviewed.

Breast Neoplasms↗