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K Nooter

Publications and source records attributed to K Nooter.

At least 73 records · Page 4Linked to original sources
PubMed1996

Expression of the multidrug resistance-associated protein (MRP) gene in primary non-small-cell lung cancer.

BACKGROUND: One of the major problems in the cure of advanced non-small-cell lung cancer (NSCLC) is its lack of response to cytotoxic drug treatment, and the mechanisms underlying this intrinsic drug resistance are unclear. PATIENTS AND METHODS: We determined the expression of a newly recognised drug resistance gene, the Multidrug Resistance-associated Protein (MRP) gene, in normal lung tissue and in tumour biopsies from 35 surgically resected NSCLCs (11 adenocarcinomas, 24 squamous cell carcinomas). MRP mRNA levels were quantitated by RNase protection assay and expression of the MRP Mr 190,000 glycoprotein was estimated by immunohistochemistry. RESULTS: Using the MRP-specific monoclonal antibody MRPr1, MRP expression was detected by immunohistochemistry in epithelial cells lining the bronchi in normal lung. In NSCLC approximately 35% of the samples showed elevated MRP mRNA levels. Based on MRP-specific immunohistochemical staining the tumours were divided into 4 groups: 12% were scored as negative (-), 14% showed weak cytoplasmic staining of the tumour cells (+/-), 40% had a clear cytoplasmic staining (+), and in 34% a strong cytoplasmic as well as membranous staining was observed (++). MRP expression, as estimated by immunohistochemistry, correlated with the MRP mRNA levels quantitated by RNase protection assay (correlation coefficient = 0.745, p = 0.0009), with MRP mRNA levels (mean +/- SD) of 3.0 +/- 1.0 U, 3.5 +/- 0.7 U, 7.5 +/- 5.9 U, and 19.3 +/- 10.7 U, in the (-), (+/-), (+), and (++) immunohistochemistry expression groups, respectively. Among the squamous cell carcinomas a correlation was observed between MRP staining and tumour cell differentiation: the strongest MRP staining was predominantly found in the well differentiated tumours. CONCLUSIONS: Hyperexpression of MRP is frequently observed in primary NSCLC, especially in the well differentiated squamous cell carcinomas. Further studies are needed to assess the role of MRP in the mechanism of clinical drug resistance in NSCLC.

ATP-Binding Cassette Transporters↗
PubMed1996

Multidrug resistance-associated protein (MRP) in haematological malignancies.

The presence of multidrug resistant cells, either acquired or de novo, severely limits treatment outcome in haematological malignancies. Although expression of the Mr 170,000 P-glycoprotein drug pump is likely to play a role in multidrug resistance (MDR) in haematological malignancies, it is now evident that other MDR mechanisms may be operational as well in leukaemias, lymphomas, and multiple myeloma. We determined the expression of a newly recognised drug resistance gene, the Multidrug Resistance-associated Protein (MRP) gene, in peripheral blood cells from healthy volunteers and from patients with haematological malignancies. Expression of MRP mRNA and its Mr 190,000 glycoprotein were estimated by RNase protection assay and immunocytochemistry, respectively. MRP appeared to be ubiquitously expressed at low levels in all nonmalignant haemopoietic cell types. However, some leukaemias showed elevated levels of MRP, probably due to transcriptional activation or increased mRNA stability. High to very high MRP expression levels were frequently found in chronic lymphocytic leukaemia and prolymphocytic leukaemia. Acute myelocytic leukemia often exhibited low but occasionally high MRP expression levels, while in the other acute and chronic leukaemias, lymphomas, and multiple myeloma, predominantly low, basal levels of MRP were found. We conclude that hyperexpression of MRP is observed in leukaemias, and that further studies are needed to assess the clinical relevance of MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Absence of human papillomavirus DNA from esophageal carcinoma as determined by multiple broad spectrum polymerase chain reactions.

Strong evidence has implicated human papillomaviruses (HPV) in the pathogenesis of anogenital cancers and a number of other mucosal and cutaneous lesions. Data concerning the involvement of HPV in esophageal cancers are controversial. Different investigators have detected HPV types (mainly types 16 and 18) in biopsy specimens of esophageal cancers. A study was undertaken to determine whether responses to chemotherapy of advanced squamous cell carcinomas could be correlated with the HPV status. Polymerase chain reaction (PCR) amplification was used for the detection of HPV DNA in biopsies of esophageal squamous cell carcinomas treated with either surgical resection alone (n = 42) or chemotherapy followed by surgical resection (n = 21). Different general and consensus PCR primer sets, which allow the detection of most of the known as well as a number of not yet characterized HPV types, were used. HPV DNA was not detected in any of the 61 esophageal squamous cell carcinomas, suggesting that HPV infections are not likely to play a major role in the etiology of this neoplasm.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Constitutive expression of the c-H-ras oncogene inhibits doxorubicin-induced apoptosis and promotes cell survival in a rhabdomyosarcoma cell line.

Drugs used in anti-cancer chemotherapy are thought to exert their cytotoxic action by induction of apoptosis. Genes have been identified which can mediate or modulate this drug-induced apoptosis, among which are c-myc, p53 and bcl-2. Since expression of oncogenic ras genes is a frequent observation in human cancer, we investigated the effects of the c-H-ras oncogene on anti-cancer drug-induced apoptosis. Apoptosis induced by a 2 h doxorubicin exposure was measured by in situ nick translation and flow cytometry in a rat cell line (R2T24) stably transfected with the c-H-ras oncogene and in a control cell line (R2NEO) transfected only with the antibiotic resistance gene neo. Both cell lines (R2T24 and R2NEO) had nearly identical growth characteristics, including cell doubling time, distribution over the cell cycle phases and plating efficiency in soft agar. Doxorubicin exposure of the R2NEO cells led to massive induction of apoptosis. In contrast, R2T24 cells, expressing the c-H-ras oncogene, showed significantly less apoptosis after doxorubicin incubation. Doxorubicin induced approximately 3- to 5-fold less cytotoxicity in the R2T24 cells than in the R2NEO cells, as determined by clonogenic assay in soft agar. No difference was observed in intracellular doxorubicin accumulation between the two cell lines, indicating that the classical, P-glycoprotein-mediated multidrug resistance phenotype is not involved in the observed differences in drug sensitivity. In conclusion, our data show that constitutive expression of the c-H-ras oncogene suppresses doxorubicin-induced apoptosis and promotes cell survival, suggesting that human tumours with ras oncogene expression might be less susceptible to doxorubicin treatment.

Animals↗
PubMed1995

Multidrug resistant cells with high proliferative capacity determine response to therapy in acute myeloid leukemia.

High spontaneous proliferation of acute myeloid leukemia (AML) in vitro is an unfavorable, tumor-specific prognostic factor. We investigated the frequency of drug-resistant tumor cells with high proliferating capacity in de novo AML and analyzed the expression of multiple resistance parameters in relation to the response to chemotherapy and overall survival. Thirty-eight patients were included in this study. P-glycoprotein (P-gp) expression was found in 28/38 patients and was associated with lower intracellular accumulation of DNR (P = 0.0001). Thirty-five out of 38 patients were treated with 1-2 regimens of daunorubicin (DNR)/cytarabine (Ara-C), and 57% attained a complete remission (CR). Failure to achieve a CR correlated with autonomous growth (P = 0.0064), CD34 and P-gp expression alone (P = 0.0005 and P = 0.048 respectively), and with simultaneous expression of P-gp and CD34 (P = 0.0001), but not with expression of the non-P-gp drug resistance associated-protein (p110), the multidrug resistance-associated protein (MRP), Ara-CTP formation or Ara-C incorporation, respectively. AML cells with CD34/P-gp double expression were more frequently observed in samples with high autonomous growth (P = 0.003). The median survival was 6 months in CD34+/P-gp+ patients as compared with 15 months in other AML patients (P = 0.003). In patients with de novo AML who fail on chemotherapy, a population of autonomously proliferating, immature AML cells with a multidrug resistant phenotype can be recognized. These cells thus show primary resistance to chemotherapy and have the potential for rapid regrowth, leading to resistant disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Expression of the multidrug resistance-associated protein (MRP) gene in human cancers.

We determined the expression of a newly recognized drug resistance gene, the multidrug resistance-associated protein (MRP) gene, [Cole et al., Science (Washington DC), 258: 1650-1654, 1992], in normal human tissues and in >370 human tumor biopsies using a quantitative RNase protection assay and immunohistochemistry. MRP mRNA appeared to be ubiquitously expressed at low levels in all normal tissues, including peripheral blood, the endocrine glands (adrenal and thyroid), striated muscle, the lymphoreticular system (spleen and tonsil), the digestive tract (salivary gland, esophagus, liver, gall bladder, pancreas, and colon), the respiratory tract (lung), and the urogenital tract (kidney, bladder, testis, and ovary). The human cancers analyzed could be divided into three groups with regard to MRP expression. Group 1 consists of tumors that often exhibit high to very high MRP mRNA levels (e.g., chronic lymphocytic leukemia). Group 2 comprises the tumors that often exhibit low, but occasionally exhibit high MRP mRNA expression (e.g., esophagus squamous cell carcinoma, non-small cell lung cancer, and acute myelocytic leukemia). Group 3 comprises the tumors with predominantly low levels of MRP mRNA, comparable to the levels found in normal tissues (e.g., other hematological malignancies, soft tissue sarcomas, melanoma, and cancers of the prostate, breast, kidney, bladder, testis, ovary, and colon). Using the MRP-specific mAbs MRPr1 and MRPm6, we confirmed the elevated MRP mRNA levels in tumor tissues by immunohistochemistry. We conclude that hyperexpression of MRP is observed in several human cancers, and that additional studies are needed to assess the clinical relevance of MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Clinical relevance of P-glycoprotein expression in haematological malignancies.

Although, generally speaking, haematological malignancies are chemotherapy-responsive tumours and high remission induction rates are obtained, disease-related death is the rule rather than the exception. The appearance of cell populations, resistant to multidrug-based chemotherapy, constitutes the major problem to achieve cures in these patients. Advances in cell biology have partly contributed to the elucidation of different multidrug resistance (MDR) mechanisms, which enable cells to survive the cytotoxic effects of multiple chemotherapeutic agents. Of these resistance mechanisms, the one that is referred to as classical MDR is the most extensively studied, both in the laboratory as well as in patients, and here we will focus on its clinical relevance in haematological malignancies. The classical MDR phenotype is caused by enhanced cellular drug efflux due to increased activity of a membrane-bound glycoprotein (P-glycoprotein) drug pump, that can pump out anthracyclines, anthracenediones, vinca alkaloids and epipodophyllotoxins, thereby actively lowering the intracellular drug concentrations to sublethal levels. As soon as molecular probes for the detection of MDR cells became available, clinical studies were initiated to answer three main questions. Do human tumor cells express P-glycoprotein? If so, is the expression indicative of a bad prognosis, c.q. resistant disease? And last but not least, can we interfere with the P-glycoprotein drug pump in the patient? Clinical data indicate that classical MDR may be involved in the development of drug resistance, especially in some haematological malignancies, such as acute myelocytic leukaemia (AML), non-Hodgkin's lymphomas (NHL), and multiple myelomas (MM). In almost all types of haematological malignancies, either untreated or treated, elevated P-glycoprotein levels have been reported, ranging from low to high. However, the acquisition of clinical MDR associated with P-glycoprotein expression occurs only in those diseases (for example, AML and MM) that are heavily treated with MDR-related drugs, probably by selection of pre-existing P-glycoprotein-expressing malignant cells. Since P-glycoprotein is found to be expressed on the membrane of normal haemopoietic progenitor cells as well, it seems likely that P-glycoprotein-positive haematological tumours develop by malignant transformation of P-glycoprotein-expressing normal haemopoietic counterparts. Especially for AML, convincing data have been reported in the literature to show that P-glycoprotein expression at diagnosis is a bad prognostic factor that predicts refractoriness. Using in vitro model systems for classical MDR, a large number of agents have been identified that can circumvent P-glycoprotein-mediated drug resistance, the so-called resistance modifying agents (RMA).(ABSTRACT TRUNCATED AT 400 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

High expression of the multidrug resistance-associated protein (MRP) in chronic and prolymphocytic leukaemia.

The expression of the multidrug resistance-associated protein (MRP), a new glycoprotein involved in drug resistance, was investigated in tumour samples from 80 patients with chronic B-cell malignancies by a quantitative RNase protection assay. In B-cell chronic lymphocytic leukaemia (B-CLL) (n = 32), either treated (n = 18) or untreated (n = 14), a high percentage of patients (20/32: 63%) had relatively high expression levels of the MRP gene (25U or more). In addition, hyperexpression of the MRP gene was demonstrated in 4/10 (40%) untreated patients with B-cell prolymphocytic leukaemia (B-PLL). In contrast, low MRP mRNA expression levels were detected in hairy cell leukaemia (n = 7), non-Hodgkin's lymphoma (n = 13) and multiple myeloma (n = 18). Statistical analysis of MRP expression in untreated CLL (mean +/- SD 29.2 +/- 18.5 U) versus treated CLL (mean +/- SD 26.7 +/- 13.7 U) did not show significant differences in MRP expression between the two groups. Southern blot analysis did not reveal amplification of the MRP gene in the leukaemia samples with elevated MRP mRNA levels. We conclude that B-PLL and B-CLL frequently display high MRP expression and that this hyperexpression is probably due to transcriptional activation and/or increased mRNA stability.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Expression of the multidrug resistance-associated protein (MRP) in acute and chronic leukemias.

We determined the expression of the multidrug resistance-associated protein (MRP), a new putative transmembrane drug transporter, in peripheral blood cells from healthy volunteers as well as from 60 patients with acute or chronic leukemia, using an RNase protection assay. MRP appeared to be ubiquitously expressed at low levels in all nonmalignant hemopoietic cell types, reflecting its basal constitutive expression. In acute myelocytic leukemia (AML) (n = 16), one of nine untreated patients and two of seven patients with prior chemotherapy showed significant hyperexpression of MRP. In chronic lymphocytic leukemia (CLL) (n = 21), either treated (n = 8) or untreated (n = 13), a high percentage (15 of 21: 71% had relatively high expression levels of the MRP gene. In contrast, low MRP expression levels were detected in acute lymphocytic leukemia (n = 14), and in chronic myelocytic leukemia (n = 9). DNA analysis by Southern blotting did not reveal amplification of the MRP gene in the leukemia samples, including those with elevated MRP mRNA levels. We conclude that relatively high expression of MRP is occasionally observed in AML and at high frequency in CLL, irrespective of treatment, probably due to transcriptional activation and/or increased mRNA stability.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Predominance of functional multidrug resistance (MDR-1) phenotype in CD34+ acute myeloid leukemia cells.

The expression of the MDR-1-encoded P-170 glycoprotein (P-170) associated with clinical multidrug resistance (MDR) was investigated in 52 consecutive patients with untreated acute myeloid leukemia (AML). P-170 expression was analyzed in correlation with CD34 expression and clinical response. Thirty of 52 patients expressed P-170 (58%). Eight of 30 P-170+ as compared with 16 of 22 P-170- patients achieved a complete remission (CR) (27% v 73%, P = .003). In 21 of 30 P-170+ patients, expression of the CD34 antigen was observed in greater than 10% of the blast cells, as compared with 14 of 22 P-170- patients (70% v 64%, P > .05). The CR rate of CD34+ and CD34- patients was 31% and 76%, respectively (P = .006). In AMLs that simultaneously expressed both P-170 and CD34, the CR rate was worse as compared with those negative for P-170 and CD34 (5% v 63%, P = .004). In 12 patients (8 P-170+, 4 P-170-) CD34 and P-170 expression were further characterized by double fluorescence studies. It was shown that P-170+ cells were largely, but not exclusively, restricted to the CD34+ cell population. For the 8 P-170+ AML samples, the median ratio of P-170+/P-170- in CD34+ cells was 4.845 (range, 0.60 to 25.00) as compared with 0.135 (range, 0.02 to 0.67) in CD34- cells. In these 12 AML samples, the presence of functional resistance as defined by reduced daunorubicin accumulation was evaluated in CD34+ and CD34- AML cells. In 8 of 8 P-170+ patients, intracellular daunorubicin accumulation in CD34+ AML blast cells was lower than in CD34- cells, and it increased after cyclosporin addition. No difference of intracellular daunorubicin accumulation was observed between CD34+ and CD34- AML cells of 4 P-170- patients. These data indicate that P-170 expression in AML with a heterogeneous CD34+ phenotype seems predominantly present in CD34+ AML blast cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Multidrug resistance (MDR) genes in haematological malignancies.

The emergence of drug resistant cells is one of the main obstacles for successful chemotherapeutic treatment of haematological malignancies. Most patients initially respond to chemotherapy at the time of first clinical admission, but often relapse and become refractory to further treatment not only to the drugs used in the first treatment but also to a variety of other drugs. Laboratory investigations have now provided a cellular basis for this clinical observation of multidrug resistance (MDR). Expression of a glycoprotein (referred to as P-glycoprotein) in the membrane of cells made resistant in vitro to naturally occurring anticancer agents like anthracyclines, Vinca alkaloids and epipodophyllotoxins, has been shown to be responsible for the so-called classical MDR phenotype. P-glycoprotein functions as an ATP-dependent, unidirectional drug efflux pump with a broad substrate specificity, that effectively maintains the intracellular cytotoxic drug concentrations under a non-cytotoxic threshold value. Extensive clinical studies have shown that P-glycoprotein is expressed on virtually all types of haematological malignancies, including acute and chronic leukaemias, multiple myelomas and malignant lymphomas. Since in model systems for P-glycoprotein-mediated MDR, drug resistance may be circumvented by the addition of non-cytotoxic agents that can inhibit the outward drug pump, clinical trials have been initiated to determine if such an approach will be feasible in a clinical situation. Preliminary results suggest that some haematological malignancies, among which are acute myelocytic leukaemia, multiple myeloma and non-Hodgkin's lymphoma, might benefit from the simultaneous administration of cytotoxic drugs and P-glycoprotein inhibitors. However, randomised clinical trials are needed to evaluate the use of such resistance modifiers in the clinic.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Circumvention of chemotherapy-induced myelosuppression by transfer of the mdr1 gene.

Drug-induced myelosuppression is a frequent reason for curtailing chemotherapy in cancer patients. 'Rescue' of myelosuppressed patients with autologous marrow transplants is reasonably advanced and permits an increase in the dose of anticancer drugs. Despite this improvement, patients often relapse with drug resistance disease. The human multidrug resistance (mdr1) gene might make it possible to render hemopoietic stem cells resistant to anticancer drugs after transfer of this gene. By introducing resistant stem cells into patients it might be possible to treat these patients repeatedly with otherwise ablative therapy. This review explores the feasibility of mdr1 gene therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

High expression of the multidrug resistance P-glycoprotein in high-risk myelodysplasia is associated with immature phenotype.

The expression of the multidrug resistance (MDR-1) gene product, P-170 glycoprotein (P-170) was investigated in 26 patients with low-risk (n = 9) or high-risk (n = 17) myelodysplastic syndrome (MDS), using a panel of monoclonal antibodies to P-170 (C219, JSB1, C494, MRK16) and quantitative analysis of MDR-1 mRNA. P-170 membrane staining was demonstrated in bone marrow blast cells of 14/17 HR-MDS and in 2/9 LR-MDS patients (p < 0.01). P-170 expression was associated with the presence of blast cells characterized by an immature or early myeloid phenotype as defined by CD34 expression (p = 0.034), CD13 or CD33 expression (p = 0.0006), or CD13/33 plus terminal deoxynucleotidyl transferase (TdT) double expression (p = 0.04). With double fluorescence analysis, P-170 expression was observed in a subset of CD34+ cells, but not in CD34- cells. P-170 expression was present in 13/15 (86%) patient samples with an abnormal karyotype as compared with 3/10 samples (30%) with a normal karyotype (p < 0.05). Nine of these 15 patients had a loss or a deletion of chromosome 7. Thirteen out of 16 (81%) MDR-1 positive patients developed acute leukemia versus two of ten (20%) MDR-1 negative patients (p = 0.025). It is concluded that MDR-1 expression in MDS is present in cells with an immature phenotype and is frequently observed in patients who have an abnormal karyotype and a high risk of leukemic transformation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Modulation of multidrug-resistant multiple myeloma by cyclosporin. The Leukaemia Group of the EORTC and the HOVON.

Resistance to chemotherapy in refractory multiple myeloma is frequently associated with expression of multidrug resistance (MDR). In resistant cells, intracellular accumulation of doxorubicin and vincristine does not occur because the MDR-1 gene product, a membrane glycoprotein (PgP), is an energy-dependent efflux pump. Cyclosporin is one of several non-cytotoxic drugs that can block the function of PgP. In a prospective study, we assessed the possibility that cyclosporin could be used clinically to modulate MDR. We studied 21 patients with multiple myeloma; disease had progressed during primary chemotherapy in 6 and was resistant to VAD (vincristine, doxorubicin, dexamethasone) in 15. The patients received cyclosporin by continuous infusion during VAD treatment; there were three cyclosporin dosage groups (5, 7.5, 10 mg/kg daily). Serum cyclosporin concentrations adequate for MDR modulation were reached in all patients receiving 7.5 or 10 mg/kg daily. 47% (7) of the VAD-refractory patients and 48% (10) of the whole group responded to VAD. Before treatment, MDR-1 expression was present in 12 patients. After VAD plus cyclosporin, no MDR-1-positive plasma cells were present in 6 of 8 patients tested. The response rate in MDR-1-positive patients was 58% compared with 33% in all our patients. Toxic effects were mild and reversible and did not include nephrotoxic or serious cardiovascular side-effects. 12 months after the start of treatment, survival was 85%, and disease-free survival at a median of 9 months after the response was 65%. Thus, in multiple myeloma clinical resistance to VAD can be circumvented by cyclosporin, which enables the cytotoxic drugs to eliminate resistant myeloma cells.

Adult↗
PubMed1992

High expression of the mdr3 multidrug-resistance gene in advanced-stage chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by an often indolent course with a poor therapeutic response at advanced stage. We investigated the expression of the human multidrug resistance genes mdr1 and mdr3 in 31 patients with CLL. Using specific probes for mdr1 and mdr3 mRNA, respectively, expression of both genes could be found in 29 of 31 patients. Of those, nine had high expression of mdr1 and 13 of mdr3. Although 29 of 31 patients showed coexpression of mdr1 and mdr3, the mRNA levels were not interrelated. Prior treatment did not significantly influence the level of mdr1 or mdr3 expression. In patients with advanced CLL (Rai stage 3 + 4) the mdr3 expression was significantly higher than in early-stage CLL (Rai stage 0 to 2) (mean +/- SEM, 25.4 +/- 4.2 U v 4.2 +/- 1.1 U; P less than .0001). Such a difference was not present for mdr1 expression (21.5 +/- 4.3 U v 10.7 +/- 3.1 U; P = .09). These data indicate that advanced-stage CLL is associated with an increased mdr3 expression, which may concur with a decreased sensitivity to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

SDZ PSC 833, a non-immunosuppressive cyclosporine: its potency in overcoming P-glycoprotein-mediated multidrug resistance of murine leukemia.

Cyclosporin A (CsA, Sandimmune) is known to reverse P-glycoprotein (P-gp170)-mediated multidrug resistance as efficiently as other prototype compounds of resistance modifiers. The immunosuppressive activity and nephrotoxicity of CsA, however, may limit its clinical use. PSC-833, a new cyclosporine, exerts a similar resistance-modifying activity but lacks toxicity or immunosuppressive activity. We have tested its potency in vitro and in vivo on the L1210 leukemia cell line transfected with a full-length cDNA copy of the human mdr I gene, which showed a stable 30-fold resistance towards adriamycin as compared to the parental cell line. In vitro growth of the transfected cell was unchanged. In vivo growth was less aggressive; the survival time of inoculated mice was prolonged. In vitro, PSC-833 was at least as potent as CsA or verapamil in reversing multidrug resistance. In vivo, the drug-resistant L1210 leukemia was completely unresponsive to i.v. monotherapy with adriamycin at its maximum tolerated dose (MTD). PSC-833 enhanced the activity and toxicity of adriamycin. The MTD of adriamycin was about 3 times lower than when given alone. On this basis, the MTD of i.v. adriamycin in combination with oral PSC-833 successfully overcame refractoriness to treatment. Survival times of the mice were considerably prolonged and even some cures of leukemic mice occurred.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Quantification of mitoxantrone in bone marrow by high-performance liquid chromatography with electrochemical detection.

An analytical method for the determination of mitoxantrone in bone marrow was developed using high-performance liquid chromatography with electrochemical detection. The extraction procedure was optimized by investigating several factors which potentially could influence the recovery of mitoxantrone from bone marrow cells. The mean recovery of mitoxantrone from rat bone marrow was found to be 81.7% with a coefficient of variation 3.8%. High-performance liquid chromatography was carried out to quantitate mitoxantrone using ametantrone as internal standard. The detection limit of our analytical method amounts to 100 pg on-column, corresponding to 1 ng/ml of cell suspension containing 2 x 10(7) cells and a day-to-day variation of maximally 8%. Storage of bone marrow samples, containing mitoxantrone, for one to fourteen days resulted in a mean recovery of 94%, as compared to freshly analysed samples. Subsequently we studied the pharmacokinetics of mitoxantrone in rat bone marrow. It appeared that after an intravenous bolus injection of mitoxantrone (2.5 mg/kg) in rats, the drug accumulated in the femoral bone marrow for about four days, and thereafter gradually declined.

Animals↗