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PubMed2004

How to respond to a qui tam lawsuit.

Whistle-blowers, i.e., current or former employees who report believed fraudulent hospital claims to the government, are on the rise. The best defense? Beat investigators to the punch and do your own sleuthing.

Federal Government↗
PubMed1991

The TAM regimen prior to allogeneic and autologous bone marrow transplantation for high-risk acute lymphoblastic leukemias: a cooperative study of 62 patients.

A total of 62 patients with high-risk acute lymphoblastic leukemia (ALL) were treated with fractionated total body irradiation, high-dose cytosine arabinoside and melphalan followed by bone marrow transplantation (BMT). Thirty-six patients received allogeneic and 26 autologous BMT. Eight patients were treated in CR1, 36 in CR2 (first relapse occurring on therapy for 32), seven in further CR, 10 in relapse (five early first relapse, four second relapse and one fourth relapse) and one with refractory ALL. Severe toxicity occurred in 26 of the 62 patients (42%) and 14 died (22.5%) from non-leukemic causes. The actuarial event-free survival at 3.6 years was 28% after autologous BMT and 52% after allogeneic BMT with actuarial relapse rates of 62% and 35%, respectively. The results of this pilot study seem promising for this group of poor risk ALL, but the relapse rate remains high after autologous BMT and needs to be improved.

Adolescent↗
PubMed1994

[Improvement of clinical symptoms by UFT and TAM and a case of bone metastasis from breast carcinoma during pregnancy].

At age 35, the patient was diagnosed with left breast carcinoma (T4bN0M0, Stage IIIb) during her first pregnancy, and underwent mastectomy of the left breast and bilateral oophorectomy. Although CPA was administered as adjuvant chemotherapy after the operation, left pelvic pain developed about a year after the operation, and bone metastasis was detected from the imaging diagnosis. Then, the therapy was switched to UFT (600 mg/day) and tamoxifen (20 mg/day), which markedly relieved the pain along with bone scintiscan (NC) and simple X-P (NC). Five years have passed since the operation, and the progress is excellent. There is neither increase of pain nor adverse reactions to drugs. Furthermore, the patient received breast reconstruction operation at her strong insistence in the third year after operation, and has achieved a high quality of life (QOL).

Adult↗
PubMed1993

Investigation of the mechanism of tamoxifen-stimulated breast tumor growth with nonisomerizable analogues of tamoxifen and metabolites.

BACKGROUND: The nonsteroidal anti-estrogen tamoxifen (TAM) is the front-line endocrine treatment for breast cancer, but disease recurrence is common. Treatment failure may occur because tumors become insensitive to TAM. Alternatively, resistance may occur because tumors become stimulated rather than inhibited by TAM. TAM-stimulated growth of MCF-7 human breast tumors has been observed in athymic mice after prolonged treatment with TAM. PURPOSE: Our purpose was to examine the mechanism of treatment failure by determining whether TAM-stimulated tumors acquire the ability to excrete TAM and its anti-estrogenic metabolites or to convert them to estrogenic compounds with weakened antiestrogenic activity. METHODS: We used high-pressure liquid chromatography to quantitate TAM and its metabolites in serum and tumors from ovariectomized athymic mice and in MCF-7 cells grown in vitro. We treated tumor-bearing mice with subcutaneous sustained-release preparations of estradiol, TAM, or a nonisomerizable (fixed-ring) analogue and then assessed the activity of these compounds on TAM-inhibited parental MCF-7 tumors and on TAM-stimulated MCF-7 TAM tumors. RESULTS: We found negligible differences in intratumoral TAM levels between TAM-inhibited parental MCF-7 tumors and TAM-stimulated MCF-7 TAM variants. We did not detect metabolite E (Met E), an estrogenic TAM metabolite, in serum or tumors. Using MCF-7 cells in vitro, we determined that the (Z) isomer of Met E, the form directly produced by TAM metabolism, must be present in the cell at a concentration of over 1000 ng/g to overcome growth inhibition by physiological levels of TAM and antiestrogenic metabolites, but the (E) isomer of Met E was effective at 10 ng/g. We reasoned that conversion of Met E from the (Z) (a weak estrogen) to (E) isomer (a potent estrogen) would be required if formation of Met E were responsible for TAM-stimulated growth. However, fixed-ring TAM, which can only form (Z) Met E, was shown to be as capable as TAM of initiating and maintaining anti-estrogen-stimulated growth of MCF-7 tumors in athymic mice. CONCLUSION: Metabolism and isomerization of TAM to estrogenic compounds is not the mechanism of TAM-stimulated growth in our model. IMPLICATION: Other potential mechanisms for TAM-stimulated growth, such as estrogen receptor mutation, must be investigated so that effective strategies can be devised to control breast cancer once therapy fails.

Animals↗
PubMedDate not supplied

Sequence-dependent antagonism between tamoxifen and methotrexate in human breast cancer cells.

High-dose methotrexate (MTX) cytotoxicity is decreased in MCF-7 breast cancer cells when the chemoendocrine agent tamoxifen (TAM) is given to cells 24 hours prior to MTX (early TAM). However, when breast cancer cells are exposed to TAM 24 hours after MTX (delayed TAM), MTX cytotoxicity is enhanced by TAM. The growth of cells exposed to 10 microM TAM and 10 microM MTX alone or in combination with early TAM plus MTX had the following order: TAM > TAM (early) + MTX > MTX. The percentages of control rates for TAM, MTX, and TAM (early) + MTX are 74.71 +/- 1.36%, 22.13 +/- 2.76%, and 38.17 +/- 2.75%, respectively. The inhibitory sequence from cells exposed to MTX + TAM (delayed TAM), MTX and TAM alone is MTX + TAM (delayed TAM) > MTX > TAM; and the percentages of control rates were 16.87 87% (MTX + TAM [delayed TAM]), 25.92 +/- 2.14% (MTX), and 54.08 +/- 14.79% (TAM). These studies suggest that: (a) the interactions between TAM and MTX are sequence-dependent; (b) TAM antagonizes the effect of MTX when TAM administration precedes MTX; and (c) TAM enhances the effect of MTX when TAM administration follows MTX.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Microsomal and peroxidase activation of 4-hydroxy-tamoxifen to form DNA adducts: comparison with DNA adducts formed in Sprague-Dawley rats treated with tamoxifen.

Using rat liver microsomal preparations and peroxidase enzymes, we have investigated the formation of DNA adducts by the antiestrogen compound tamoxifen (TAM) and its metabolite 4-hydroxy-tamoxifen (4-OH-TAM). When reduced nicotinamide-adenine dinucleotide phosphate (NADPH) was used as a cofactor in microsomal activation of either 4-OH-TAM or TAM, one DNA adduct and relative DNA adduct levels of 4.6 and 3.1 x 10(-8), respectively were detected by 32P-postlabeling. The DNA adduct produced by microsomal activation of 4-OH-TAM and TAM was the same. With cumene hydroperoxide (CuOOH) as the cofactor for the microsomal activation of either 4-OH-TAM or TAM, three to six DNA adducts were produced; the relative adduct levels were 8.0 and 20.6 x 10(-8), respectively. Comparison of the DNA adduct patterns produced by 4-OH-TAM and TAM showed that they were distinct. However one of the DNA adducts (a) produced by microsomal activation of 4-OH-TAM using CuOOH was the same as adduct a produced by microsomal activation of 4-OH-TAM with NADPH. Activation of 4-OH-TAM with horseradish peroxidase resulted in the formation of a single DNA adduct and a relative adduct level of 20.7 x 10(-8). Rechromatography analysis of this DNA adduct showed that it was identical to that produced by microsomal activation of 4-OH-TAM with NADPH and one of the adducts produced using CuOOH as the cofactor. Ten DNA adducts and a relative adduct level of 15.3 x 10(-8) were detected in the liver of female Sprague-Dawley rats treated daily with 20 mg/kg of TAM for 7 days. The DNA adduct pattern in the liver of the treated animals was similar to that produced by microsomal activation of TAM using CuOOH as the co-factor. The principal DNA adduct (no. 6) formed in the livers of rats treated with TAM was the same as the principal DNA adduct formed following microsomal activation of TAM using CuOOH as a cofactor. The DNA adduct formed following microsomal activation of either TAM or 4-OH-TAM using NADPH was also present as one of the adducts (1) formed in vivo following TAM treatment. These studies demonstrate that 4-OH-TAM can be activated to form DNA adducts and that it contributes to the formation of DNA adducts in the liver of rats treated with TAM.

Animals↗
PubMed1999

The aromatase inactivator 4-hydroxyandrostenedione (4-OH-A) inhibits tamoxifen metabolism by rat hepatic cytochrome P-450 3A: potential for drug-drug interaction of tamoxifen and 4-OH-A in combined anti-breast cancer therapy.

Tamoxifen (tam), an anti-breast cancer agent, is metabolized into tam-N-oxide by the hepatic flavin-containing monooxygenase and into N-desmethyl- and 4-hydroxy-tam by cytochrome P-450s (CYPs). Additionally, tam is metabolically activated by hepatic CYP3A, forming a reactive intermediate that binds covalently to proteins. Tam and 4-hydroxyandrostenedione (4-OH-A) are currently used to treat breast cancer, and it has been contemplated that 4-OH-A be given concurrently with tam to contravene potential tumor resistance to tam. Because alterations in tam metabolism may influence its therapeutic efficacy, the effect of 4-OH-A on tam metabolism was examined. Incubation of tam with liver microsomes from phenobarbital-treated rats, in the presence of 4-OH-A (10-100 microM), resulted in marked inhibition of tam-N-demethylation and tam covalent binding and in decreased tam-N-oxide accumulation; however, there was no inhibition of the formation of 4-hydroxy-tam and of 3,4-dihydroxytamoxifen. These findings indicate that 4-OH-A inhibits CYP3A, but not P-450(s) that catalyze tam 4-hydroxylation. The diminished tam-N-oxide accumulation could be due to decreased N-oxide formation and/or due to increased N-oxide reduction. Incubation of tam-N-oxide with liver microsomes containing heat-inactivated flavin-containing monooxygenase demonstrated that 4-OH-A increases the accumulation of tam, possibly by diminishing its P-450-mediated metabolism. Kinetic studies indicate that 4-OH-A is a competitive inhibitor of CYP3A, but not a time-dependent inactivator. Consequently, the concurrent treatment of tam and 4-OH-A may result in increased tam half-life and thus could potentiate the therapeutic efficacy of tam and diminish the potential side effects of tam by inhibiting its covalent binding to proteins and possibly to DNA.

Androstenedione↗
PubMed2006

Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants.

INTRODUCTION: Tamoxifen (TAM) is an antiestrogen widely used in the treatment and prevention of breast cancer in women. One of the major mechanisms of metabolism of TAM and one of its major active metabolites, 4-hydroxytamoxifen (4-OH-TAM), is via glucuronidation. In the present study, the glucuronidating activities of three common variant isoforms encoded by the human UDP-glucuronosyltransferase (UGT) 1A4 gene were examined against TAM, trans-4-OH-TAM and cis-4-OH-TAM. METHODS: HPLC was used to detect glucuronide conjugates in microsomes from UGT1A4-overexpressing HK293 cells. The UGT1A4 wild-type cDNA was synthesized by RT-PCR using normal human liver total RNA. The UGT1A424Thr/48Leu and UGT1A424Pro/48Val variants were generated by site-directed mutagenesis of the pcDNA3.1/V5-His-TOPO plasmid expressing wild-type UGT1A424Pro/48Leu. Levels of UGT1A4 expression in UGT-overexpressing cell lines were measured by western blot analysis. RESULTS: Microsomes from wild-type UGT1A424Pro/48Leu-overexpressing HK293 cells exhibited significant levels of activity against TAM, trans-4-OH-TAM and cis-4-OH-TAM, forming exclusively the tamoxifen quaternary ammonium glucuronide (TAM-N+-glucuronide) and the 4-hydroxytamoxifen quaternary ammonium glucuronides (trans-4-OH-TAM-N+-glucuronide and cis-4-OH-TAM-N+-glucuronide) with apparent Km values of 2.0 microM, 2.2 microM, and 2.1 microM, respectively. Higher glucuronidation activities were found by kinetic analysis for microsomes from the variant UGT1A424Pro/48Val-overexpressing cell line as compared with microsomes from wild-type UGT1A424Pro/48Leu-overexpressing cells against TAM and against both the trans and cis isomers of 4-OH-TAM. A significantly (P < 0.02) lower Km value (approximately 1.6-fold to 1.8-fold) was observed for both 4-OH-TAM isomers, while a near-significant (P = 0.053) decrease in Km was observed for TAM for the UGT1A424Pro/48Val variant as compared with wild-type UGT1A4. The Vmax/Km ratio for the UGT1A424Pro/48Val variant was significantly (P < or = 0.005) higher than that observed for the wild-type UGT1A4 isoform for both the trans and cis isomers of 4-OH-TAM after normalization for UGT1A4 expression by western blotting. No significant effect on enzyme kinetics was observed for the UGT1A424Thr/48Leu variant against either isomer of 4-OH-TAM or with TAM. CONCLUSION: These data suggest that the UGT1A4 codon 48 Leu>Val polymorphism significantly alters glucuronidation rates against TAM and its active hydroxylated metabolites, and that this polymorphism may play an important role in individual pharmacological response to TAM therapy.

Glucuronates↗