Response of brain specific microenvironment to P-glycoprotein inhibitor: an important factor determining therapeutic effect of P-glycoprotein inhibitor on brain metastatic tumors

P-glycoprotein (P-gp), a factor responsible for the multidrug resistance of tumors, is specifically expressed in brain microenvironment. To test its roles in brain metastatic tumor chemoresistance, we implanted the paclitaxel-sensitive melanoma cell line, K1735, into the skin or brain of mice and examined its paclitaxel resistances. When implanted into the skin, paclitaxel inhibited tumor growth, however, it had no inhibitory effect on cells implanted into the brain. The paclitaxel resistance of the brain K1735 tumors was eliminated by combined treatment with a P-gp inhibitor, HM30181A, and paclitaxel. Previously we found that there is a defined therapeutic window for combined treatment of brain tumors with HM30181A and paclitaxel. To determine whether it is due to responses of the brain microenvironment we measured changes in P-gp expression and function of brain endothelial cells in response to HM30181A treatment in vitro and in vivo. They were significantly increased by high-dose HM30181A treatment and it was related with the therapeutic effect loss of high-dose HM30181A treatment. Therefore, P-gp in the brain microenvironment has crucial roles in the brain metastatic tumor chemoresistance and brain microenvironment responses to P-gp inhibitor treatment should be considered in the development of brain endothelial cell-targeted chemotherapy using P-gp inhibitor.     

Tamoxifen Paradoxically Decreases Paclitaxel Deposition into Cerebrospinal Fluid of Brain Tumor Patients

Summary Background: P-glycoprotein (Pgp) mediates, in part, resistance to natural product chemotherapy drugs which constitute over half of the available drugs for cancer treatment. Tamoxifen (TAM) enhances intracellular deposition of natural product chemotherapy in human cell lines by inhibition of Pgp. Pgp is highly expressed in the choroid plexus and is thought to be a key component of the blood–cerebrospinal fluid barrier (BCSFB). We conducted a prospective, randomized study to assess if Pgp inhibition by TAM alters deposition of paclitaxel in cerebrospinal fluid (CSF). Methods: Ten patients with either primary or metastatic brain tumors were randomized to: paclitaxel alone (175 mg/m²/IV) or a course of TAM (160 mg/m² PO BID on Days 1–5) followed by paclitaxel (175 mg/m²/IV on Day 5). CSF and plasma samples were obtained following paclitaxel infusion; paclitaxel and TAM concentrations were measured by high-performance liquid chromatography assays. Results: Paclitaxel was detected in the CSF of six of the 10 patients. Peak CSF paclitaxel concentrations of the paclitaxel and paclitaxel–TAM groups ranged between 3.5–57.4 and 2.3–24.6 nM, respectively. Though there was a 2.4-fold higher mean CSF paclitaxel concentration and a 3.7-fold higher median peak CSF:plasma paclitaxel ratio for those who received paclitaxel alone as compared to combined paclitaxel–TAM, it was not statistically significant (P = 0.22). In one patient enrolled to both arms, higher CSF concentrations of paclitaxel and higher paclitaxel CSF: plasma ratios were observed when given paclitaxel alone. Conclusions: The trend towards lower paclitaxel CSF concentrations when given with TAM is consistent with the published finding that Pgp’s localization in the endothelial cells of the choroid plexus works in an opposite direction and keeps drugs in the CSF. Thus, agents which inhibit Pgp, such as TAM, may increase efflux of Pgp substrates out of the BCSFB and may paradoxically lower CSF concentrations of natural product chemotherapy drugs. Conceptually, this finding implies that the Pgp in the BBB and BCSFB keeps natural toxins such as paclitaxel, from entering the brain (BBB) and, if they do enter the brain, keeps them in the CSF (BCSFB) where they may be less harmful than if they re-entered the brain. Thus, our work supports this novel idea and adds to the understanding of the functions of the BCSFB.     

The effect of P-glycoprotein on paclitaxel brain and brain tumor distribution in mice

It may be inferred from the presence of P-glycoprotein (Pgp) in brain capillaries that this drug efflux pump is a factor in limiting the penetration of certain agents into brain tumors. However, by contrast with normal brain capillaries which constitute the blood-brain barrier, brain tumor capillaries are compromised or "leaky," and the extent to which Pgp expression in brain tumor neovasculature retains its capacity to limit drug penetration has not been determined. To address this question, we studied the normal brain and brain tumor distribution of paclitaxel (PAC), a known Pgp substrate, using steady-state PAC dosing regimens in wild-type and Pgp knockout (mdr1a -/- and mdr1b -/-) mice bearing an intracerebral B-16 melanoma. At comparable steady-state PAC plasma concentrations of approximately 5 microg/ml, steady-state PAC brain concentrations in Pgp knockout mice were approximately 3-, 1.8-, and 1.7-fold greater in left brain, right brain, and brain tumor, respectively, than in wild-type mice and statistically different (P < 0.05) in each brain region. Determination of the steady-state brain/plasma concentration ratios or partition coefficients, which take into account any differences in plasma concentrations between each group, indicated a similar pattern as did the absolute brain concentrations. It is concluded that even in the neovasculature of brain tumors, Pgp has the facility to limit drug penetration, although somewhat less so than in normal brain.     

Fetal antigen 2 in primary and secondary brain tumors.

Immunohistochemical deposition and distribution of fetal antigen 2 (FA2) was examined in normal brain tissue and in primary and metastatic tumors of the brain. In normal brain tissue FA2 was exclusively found linearly around the vessels, along pia and in arachnoidea. A similar localization was seen in primary brain tumors except in gliosarcoma where FA2 was distributed diffusely in the sarcoma region and was absent in the glioma region. In metastatic carcinoma with tumor stroma a diffuse staining reaction was seen in the stroma and with a basement membrane (BM) like staining at the tumor cell/stroma interface. Intracytoplasmic FA2 staining of the tumor cells was seen in areas without tumor stroma. In metastatic melanoma a BM like FA2 staining was seen around and between individual tumor cells. The staining patterns seen in the metastatic tumors were in accordance with that of the corresponding primary tumors.     

P-glycoprotein expression in brain tumors

Summary Overexpression of P-glycoprotein (P-gp) in cancer cells can result in resistance to several chemotherapy agents (multidrug resistance) including doxorubicin and vincristine. The drugs to which resistance develops also penetrate the blood brain barrier poorly. P-gp expression in brain capillary endothelial cells suggests that P-gp may restrict drug entry into brain tumors and thus be another mechanism of drug resistance. To seek evidence for either of these roles in the drug resistance of brain tumors, we examined the location of expression of P-gp in 49 brain tumors, using an anti-P-gp mouse monoclonal antibody and immunohistochemistry. P-gp expression was observed in tumor cells of two glioblastomas and a meningeal sarcoma but not in low-grade primary or metastatic tumors. In low-grade primary tumors, P-gp was present in all vascular endothelial cells. In the vascular endothelial cells of anaplastic primary brain tumors and brain metastases, P-gp expression was heterogeneous or absent. These findings are consistent with a role for P-gp in the resistance of some brain tumors to chemotherapy agents.     

Oral paclitaxel chemotherapy for brain tumors: ideal combination treatment of paclitaxel and P-glycoprotein inhibitor

Oral chemotherapy has many advantages over parenteral chemotherapeutics administration. To use the advantages of the oral chemotherapy and maximize anti-tumor effects of the chemotherapeutic agent, we designed HM30181A (a P-glycoprotein inhibitor) and a paclitaxel oral co-administration chemotherapeutic method. HM30181A is used to aid paclitaxel absorption from gut lumen into blood and to inhibit paclitaxel exclusion out of the brain tumor mass by endothelial cells, which inhibits paclitaxel access to tumor cells in the brain parenchyma. We applied HM30181A and paclitaxel oral co-administration methods to the treatment of tumors in the brain using the K1735 melanoma brain metastasis animal model and the U-87 MG glioblastoma animal model. Administrations were performed twice per week for 28 days and the therapeutic effect was examined using tumor volume change. We observed that 32 mg/kg HM30181A and 16 mg/kg of paclitaxel (dose ratio 2:1) oral co-administration showed significant therapeutic effects in both animal models, but when the doses or dose ratio was changed, the effects could not be observed. Therefore, adjustments of doses and dose ratio of the agents seems to be essential in realizing oral HM30181A and paclitaxel treatment in brain tumors. These results suggest that if the doses and dose ratio can be successfully adjusted, the oral co-administration of HM30181A and paclitaxel can be used to treat tumors in the brain.     

Vascular gene expression patterns are conserved in primary and metastatic brain tumors

Malignant primary glial and secondary metastatic brain tumors represent distinct pathological entities. Nevertheless, both tumor types induce profound angiogenic responses in the host brain microvasculature that promote tumor growth. We hypothesized that primary and metastatic tumors induce similar microvascular changes that could function as conserved angiogenesis based therapeutic targets. We previously isolated glioma endothelial marker genes (GEMs) that were selectively upregulated in the microvasculature of proliferating glioblastomas. We sought to determine whether these genes were similarly induced in the microvasculature of metastatic brain tumors. RT-PCR and quantitative RT-PCR were used to screen expression levels of 20 candidate GEMs in primary and metastatic clinical brain tumor specimens. Differentially regulated GEMs were further evaluated by immunohistochemistry or in situ hybridization to localize gene expression using clinical tissue microarrays. Thirteen GEMs were upregulated to a similar degree in both primary and metastatic brain tumors. Most of these genes localize to the cell surface (CXCR7, PV1) or extracellular matrix (COL1A1, COL3A1, COL4A1, COL6A2, MMP14, PXDN) and were selectively expressed by the microvasculature. The shared expression profile between primary and metastatic brain tumors suggests that the molecular pathways driving the angiogenic response are conserved, despite differences in the tumor cells themselves. Anti-angiogenic therapies currently in development for primary brain tumors may prove beneficial for brain metastases and vice versa.     

Clinical trial of MCNU for malignant brain tumors

A total of 71 cases with primary brain tumors (44 cases) and metastatic brain tumors (30 cases) were entered into our clinical studies with MCNU and radiation therapy or MCNU alone. With regard to tumor reduction on CT scan, the response rates obtained for MCNU and radiation were 21.7% for malignant gliomas and 50.0% for metastatic brain tumors. With regard to improvement of neurological signs, the response rates obtained for MCNU and radiation were 62.9% for malignant gliomas and 71.4% for metastatic brain tumors. The response rates for MCNU were 5.8% for malignant gliomas and 46.1% for metastatic brain tumors. In the improvement of performance status, the response rates for MCNU and radiation were 51.8% for malignant gliomas and 64.2% for metastatic brain tumors. The response rates for MCNU were 46.1% for malignant gliomas and 30.7% for metastatic brain tumors. A minimal degree of hematological toxicity occurred but this gradually disappeared. These results suggested that MCNU has relatively effective antitumor activity against metastatic brain tumors and an enhanced effect with radiation against malignant gliomas.     

Distribution of cis-diamminedichloroplatinum in patients with metastatic brain tumors after intravenous or intracarotid administration

The distribution of cis-diamminedichloroplatinum (CDDP) was studied in 21 patients with intracerebral metastatic brain tumors from lung cancer after CDDP 100 mg/sq m i.v. or i.a. administration for 20 minutes using an infusion pump during surgery. Surgical tissue specimens of tumor and edematous brain tissue adjacent to tumor were obtained with whole blood soon after CDDP administration and assayed for total platinum using an atomic absorption spectrophotometer. The pharmacological distribution rates were represented as the brain/plasma, tumor/plasma and tumor/brain ratios. No statistical differences in the CDDP concentrations in the plasma were found between i.a. and i.v. administrations. The platinum concentration in edematous brain tissue adjacent to the tumor was always lower than the platinum concentration in the metastatic intracerebral tumor. No differences were noted for the brain/plasma ratio in the brain tissue adjacent to the tumor between the two administration methods (i.a.: 0.38 +/- 0.09, n = 8; i.v.: 0.43 +/- 0.13, n = 11, M +/- S.E.). However, two cases who each underwent two different administration courses showed i.a. to be pharmacologically advantageous since it resulted in a 2-to-7 times higher concentration in the brain tissue adjacent to the tumor. The tumor/plasma and tumor/brain ratios for i.a. administration (1.72 +/- 0.26, 6.09 +/- 1.30, n = 8, M +/- S.E.) were two times higher than those for i.v. administration 0.90 +/- 0.23, n = 12, 3.40 = 0.59, n = 10, M +/- S.E. (p less than 0.05, p = 0.061, unpaired t-test). Toxic side effects were moderate, especially decreased creatinine clearance, but tolerable. Our preliminary results demonstrated the pharmacologic advantage of i.a. CDDP chemotherapy in the treatment of metastatic brain tumor patients.     

Growth rates of metastatic brain tumors in nonsmall cell lung cancer

BACKGROUND: The purpose of the study was to evaluate the growth kinetics of metastatic brain tumors during chemotherapy and to analyze growth rates and volumetric doubling time of metastatic brain tumors in patients with nonsmall cell lung cancer (NSCLC) with tumor regrowth. METHODS: NSCLC patients with minimally symptomatic brain metastases who were not treated previously were enrolled. Serial magnetic resonance images (MRI) of 30 metastatic brain tumors in 19 patients were reviewed. Tumor growth rates and volumetric tumor doubling time of tumor regrowth were estimated. All patients were treated with front-line chemotherapy until disease progression. RESULTS: The median tumor growth rate was 12.10 mm(3)/day (interquartile range [IQR], 3.09-36.75). The volume percentage increase/day was 1.67 (IQR, 0.69-4.59). The median volumetric tumor doubling time was 58.48 days (IQR, 32.33-98.48). CONCLUSIONS: These findings may help optimize patient management during follow-up. Study results indicated that brain MRI should be obtained at a minimum of 2-month intervals to screen for metastatic brain tumors.     

非小细胞肺癌原发灶与脑转移灶EGFR基因突变状况的一致性研究

目的 探讨非小细胞肺癌（NSCLC）原发灶与脑转移灶的表皮生长因子受体（EGFR）基因突变状况,分析两者之间是否存在一致性。方法 收集2003年1月至2011年12月31例NSCLC脑转移患者的肺原发灶和脑转移灶石蜡包埋组织标本,应用DNA直接测序法进行EGFR突变分析,如发现两者突变不一致则进一步采用增殖阻碍突变系统 （ARMS）验证。结果 31例NSCLC肺原发灶中,8例存在19外显子E746-A750缺失突变、4例为21外显子L858R点突变;在31例脑转移灶样本中,8例为19外显子E746-A750缺失突变,3例存在21外显子L858R点突变,EGFR突变类型在脑转移灶和肺原发灶的分布差异无统计学意义 （P=0.793）。共有16.1％ （5／31）的肺原发灶和脑转移灶EGFR突变状况不一致,其中男性4例,女性1例;3例腺癌 （2例脑转移灶19外显子缺失突变而肺原发灶阴性突变,1例肺原发灶21外显子点突变而脑转移灶阴性突变）,1例鳞癌和1例非典型类癌 （均为脑转移灶阴性突变而肺原发灶19外显子缺失突变）。结论 NSCLC原发病灶及脑转移灶EGFR基因突变存在不一致性。     

Tamoxifen Modulation of Etoposide Cytotoxicity Involves Inhibition of Protein Kinase C Activity and Insulin-Like Growth Factor II Expression in Brain Tumor Cells

Tamoxifen, a non-steroidal anti-estrogen widely used against breast cancer, is also useful for treatment of other malignancies, due to its sensitizing effect on other chemotherapeutic agents and radiation. We have investigated the advantages of combining tamoxifen with one of the commonly used cancer chemotherapeutic drug, etoposide (VP-16) in brain tumor cell lines. While tamoxifen (10 microM) increased etoposide cytotoxicity 8.3-fold in the human glioma cell line (HTB-14), it increased etoposide cytotoxicity 47.5- and 40-fold in two primary cell lines established from pediatric medulloblastoma patients (MCH-BT-31 and MCH-BT-39), respectively. Similarly, in the pediatric ependymoma cell lines (MCH-BT-30 and MCH-BT-52), tamoxifen enhanced etoposide cytotoxicity 6- and 2.68-fold, respectively. CalcuSyn analysis of cytotoxicity data showed that tamoxifen and etoposide combinations were synergistic with combination index values ranging from 0.243 to 0.369 at IC50 level among different pediatric brain tumor cell lines. Tamoxifen is also cytotoxic at higher concentrations (> 20 microM) in brain tumor cells. To understand the mechanism underlying the tamoxifen modulation of etoposide cytotoxicity, we analyzed expression of P-glycoprotein (P-gp), insulin-like growth factor-I receptor (IGF-IR), IGF-I, IGF-II and estrogen receptor as well as protein kinase C (PKC) activity. While P-gp, IGF-IR and IGF-I were not affected, enhanced inhibition of PKC, and IGF-II were observed in brain tumor cells treated with tamoxifen and etoposide combination as compared to cells treated with either drug alone. Tamoxifen at 10 microM when combined with etoposide at 0-100 microM concentrations reduced PKC activity 77% compared to only 58% without tamoxifen. IGF-II expression decreased to 48.6% of the untreated control in the combination treatment as compared to 31.2% for etoposide alone and 26.2% for tamoxifen alone treatments. These results suggest that inhibitory effect of tamoxifen on brain tumor cells manifest through different mechanisms involving inhibition of targets such as PKC and IGF-II.     

以颅内压增高为主症的肺癌脑转移16例分析

目的：探讨以颅内压增高为主症的肺癌脑转移的临床特点及诊断。方法：对16例以颅内压增高为主症的肺癌脑转移患者的临床表现、CT、MRI、脑脊液检查进行回顾性分析。结果：颅内压增高为主症的肺癌脑转移患者亚急性起病，进行性加重，主要表现为颅内压增高及脑膜刺激征，根据增强CT、MRI，并结合脑脊液检查及原发肿瘤灶可明确诊断。结论：肺癌脑转移以颅内压增高为主要临床表现，是早期诊断肺癌脑转移的重要线索，增强CT、MRI检查及脑脊液检查是重要的诊断依据。     

Immunohistochemical expression of E-cadherin in metastatic brain tumors

The adhesion molecule E-cadherin has been shown to influence malignant transformation of tumors, including local and distant metastases. We examined the expression of E-cadherin to determine its relationship to the development of metastasis in metastatic brain tumors. Immunohistochemistry for E-cadherin and Ki-67 was carried out in 76 formalin-fixed, paraffin-embedded archival specimens of metastatic brain tumors and in 14 corresponding available primary tumors from patients who received treatment for metastatic brain tumors. The primary tumors were mainly lung cancers (51.3%), followed by gastrointestinal tumors (28.9%). E-cadherin was expressed in 62 (81.5%) of 76 cases examined. In metastatic adenocarcinomas, a consistent tendency for E-cadherin expression was noted, regardless of the degree of differentiation or the extent of spread of the disease (P=0.4). There was a direct correlation between E-cadherin expression and high MIB-1 index in all metastatic brain tumors (P=0.0007). Pairwise analysis in 14 primary tumors and the corresponding metastatic specimens revealed high E-cadherin and MIB-1 staining in metastatic brain tumors. These results provide a unique association between E-cadherin, systemic metastasis, and proliferation potential in metastatic brain tumors.     

Influence of blood-brain barrier efflux pumps on the distribution of vincristine in brain and brain tumors

Vincristine (VCR) is efficacious in some but not all brain cancers and an established substrate of Pgp and Mrp1. However, the extent to which such transporters affect the VCR penetration through the blood-brain barrier (BBB) is poorly understood. To evaluate the role of Pgp and Mrp1 in VCR CNS distribution, VCR concentrations were analyzed under steady-state conditions in normal brain, brain tumor, and bone marrow in wild-type (WT), Mrp1 ko (mrp1−/−), Pgp ko (mdr1a−/−:mdr1b−/−), and TKO (mdr1a−/−:mdr1b−/−:mrp1−/−) mice. VCR normal brain partition coefficients (i.e. tissue/plasma VCR concentrations) in TKO mice were greater than those in WT mice at both targeted 10 and 50 ng/mL plasma VCR concentrations, and ranged from 1.3- to 3.6-fold. VCR brain tumor partition coefficients in Mrp1 mice were greater than WT mice at both doses, being 1.5- and 2.4-fold higher at low and high doses, respectively. TKO mice also showed elevated VCR brain tumor penetration with a brain tumor partition coefficient of 1.9-fold greater than that in WT mice at the high-dose level. The bone marrow partition coefficient in Mrp1 ko mice was 1.65-fold greater than that in WT mice. Within strain comparisons revealed that VCR brain tumor concentrations were significantly greater than normal brain in all strains, ranging from 9- to 40-fold. These findings indicate that disruption of the BBB caused the largest enhancement in VCR tumor concentrations, yet the absence of Mrp1 on the brain tumor vasculature could enhance the penetration compared with that in normal brain.     

Local blood-to-tissue transport in Walker 256 metastatic brain tumors

Local blood-to-tissue transfer constants (K) in metastatic Walker 256 (WL-256) brain tumors produced by the intracarotid artery injection of WL-256 tumor cells in rats were measured using ¹⁴C--aminoisobutyric acid and quantitative autoradiography. Small compact and diffuse infiltrative intraparenchymal tumors had values of K similar to that of contralateral nontumorous brain tissue. Medium and large tumors, meningeal metastases and intrave ntricular tumors had higher K values (5 to 30 fold) than contralateral nontumorous brain tissue indicating that intraparenchymal tumor size and location in meningeal and choroidal tissue influence the permeability of tumor capillaries. The local intratumor values of K varied considerably in these tumors and this variability of K correlated to only a few specific histopathologic features of the tumors. The value of K abruptly decreased at the tumor-brain interface when this interface was sharply defined, indicating that the metastatic tumors have only a small effect on the permeability of adjacent brain capillaries. Low blood-to-tumor transport of water soluble drugs will significantly affect drug concentrations in the tumor and the tumor-drug exposure.An abstract of this work has been presented: R Blasberg, C Patlak, W Shapiro, J Fenstermacher: Metastatic brain tumors: local blood flow and capillary permeability, Neurology 29:546, 1979.     

Paclitaxel (TAXOL(R)) concentrations in brain tumor tissue

BACKGROUND: Paclitaxel (Taxol^®) is a novel chemotherapeutic agent, activeagainst a variety of tumors. It is not known whether the drugpenetrates brain tumor tissue. PATIENTS AND METHODS: Three patients with a recurrent glioma received paclitaxel (175mg/m²) in a 3-hour i.v. infusion prior to surgery. Paclitaxelconcentrations were measured in the tumor tissue, cerebrospinalfluid, cyst fluid, plasma and, in one patient, normal braintissue. RESULTS: Tumor tissue concentrations were in the thera- peutic rangein all three patients. Brain tissue concentration, however,was below the detection limit of the trial. CONCLUSIONS: These findings suggest that paclitaxel may have a place in braintumor therapy. The low concentration in normal brain tissue,as observed in one patient, may suggest, however, that the drugdoes not cross the intact blood-brain barrier. brain tumor, chemotherapy, glioma, paclitaxel, tissue concentrations     

Tissue concentration of systemically administered antineoplastic agents in human brain tumors

The blood–brain-barrier (BBB) limits the penetration of many systemic antineoplastic therapies. Consequently, many agents may be used in clinical studies and clinical practice though they may not achieve therapeutic levels within the tumor. We sought to compile the currently available human data on antineoplastic drug concentrations in brain and tumor tissue according to BBB status. A review of the literature was conducted for human studies providing concentrations of antineoplastic agents in blood and metastatic brain tumors or high-grade gliomas. Studies were considered optimal if they reported simultaneous tissue and blood concentration, multiple sampling times and locations, MRI localization, BBB status at sampling site, tumor histology, and individual subject data. Twenty-Four studies of 19 compounds were included. These examined 18 agents in contrast-enhancing regions of high-grade gliomas, with optimal data for 2. For metastatic brain tumors, adequate data was found for 9 agents. Considerable heterogeneity was found in the measurement value, tumor type, measurement timing, and sampling location within and among studies, limiting the applicability of the results. Tissue to blood ratios ranged from 0.054 for carboplatin to 34 for mitoxantrone in high-grade gliomas, and were lowest for temozolomide (0.118) and etoposide (0.116), and highest for mitoxantrone (32.02) in metastatic tumors. The available data examining the concentration of antineoplastic agents in brain and tumor tissue is sparse and limited by considerable heterogeneity. More studies with careful quantification of antineoplastic agents in brain and tumor tissue is required for the rational development of therapeutic regimens.     

Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation

Background:

The intestinal uptake of the taxanes paclitaxel and docetaxel is seriously hampered by drug efflux through P-glycoprotein (P-gp) and drug metabolism via cytochrome P450 (CYP) 3A. The resulting low oral bioavailability can be boosted by co-administration of P-gp or CYP3A4 inhibitors.

Methods:

Paclitaxel or docetaxel (10 mg/kg) was administered to CYP3A4-humanised mice after administration of the P-gp inhibitor elacridar (25 mg kg⁻¹) and the CYP3A inhibitor ritonavir (12.5 mg kg⁻¹). Plasma and brain concentrations of the taxanes were measured.

Results:

Oral co-administration of the taxanes with elacridar increased plasma concentrations of paclitaxel (10.7-fold, P<0.001) and docetaxel (four-fold, P<0.001). Co-administration with ritonavir resulted in 2.5-fold (paclitaxel, P<0.001) and 7.3-fold (docetaxel, P<0.001) increases in plasma concentrations. Co-administration with both inhibitors simultaneously resulted in further increased plasma concentrations of paclitaxel (31.9-fold, P<0.001) and docetaxel (37.4-fold, P<0.001). Although boosting of orally applied taxanes with elacridar and ritonavir potentially increases brain accumulation of taxanes, we found that only brain concentrations, but not brain-to-plasma ratios, were increased after co-administration with both inhibitors.

Conclusions:

The oral availability of taxanes can be enhanced by co-administration with oral elacridar and ritonavir, without increasing the brain penetration of the taxanes.     

Distribution of tamoxifen and metabolites into brain tissue and brain metastases in breast cancer patients

We determined the amount of tamoxifen, N-desmethyltamoxifen (metabolite X), N-desdimethyltamoxifen (metabolite Z), and hydroxylated metabolites (Y, B, BX) in brain metastases from breast cancer and in the surrounding brain tissues. Specimens were collected from the breast cancer patients who received tamoxifen for 7-180 days and with the last dose taken within 28 h before surgical removal of the tumour. The concentrations of tamoxifen and its metabolites were up to 46-fold higher in the brain metastatic tumour and brain tissue than in serum. Metabolite X was the most abundant species followed by tamoxifen and metabolite Z. Small but significant amounts of the hydroxylated metabolites, trans-1(4-beta-hydroxyethoxyphenyl)-1,2-diphenylbut-1-ene (metabolite Y), 4-hydroxytamoxifen (metabolite B) and 4-hydroxy-N-desmethyltamoxifen (metabolite BX) were detected in most specimens. The ratios between the concentrations of tamoxifen and various metabolites were similar in tumour, brain and serum. This is the first report on the distribution of tamoxifen and metabolites into human brain and brain tumour, and the data form a basis for further investigation into the therapeutic effects of tamoxifen on brain metastases from breast cancer.