Search PubMed⌕ Search

Biomedical subjects

R Pieters

Publications and source records attributed to R Pieters.

At least 109 records · Page 6Linked to original sources
PubMed1998

The role of impaired transport in (pre)clinical resistance to methotrexate: insights on new antifolates.

Impaired transport appears to be a common mechanism of resistance of neoplastic cells to the antifolate methotrexate. The extensive knowledge of the molecular, biochemical and functional properties of the membrane transport systems for folates, in particular the reduced folate carrier (RFC) and membrane folate receptors (MFR), has made an important contribution to the rational design of novel antifolates that are either more efficiently internalized via these transporters or can simply bypass these transport routes. The current status of exploiting the RFC and MFR for transport of novel antifolates active in preclinical model systems and a clinical setting will be reviewed, with a special reference to childhood acute lymphoblastic leukemia (ALL) and acute non-lymphoblastic leukemia (ANLL).

Journal Article↗
PubMed1998

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia.

Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 microM PSC 833 (P = 0.025), 1.5-fold using 4 microM CsA (P = 0.003) and 1.6-fold using 6 microM Vp (P = 0.012) whereas the adverse effect of 25 microM genistein was median 1.8-fold (P < 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of P-gp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia--implications for treatment of infants.

The prognosis of infant ALL, characterized by a high incidence of the immature CD10 negative B-lineage ALL (proB ALL) is poor. This study aimed to determine the resistance profile of infant ALL cells. In vitro drug resistance was determined by the MTT assay of 395 children with ALL at initial diagnosis: there were 21 infants <1.5 years of which nine <1 year, 284 children aged 1.5-10 years (intermediate age group) and 90 children >10 years. Immunophenotyping resulted in 310 cALL/preB ALL, 69 T-ALL, 15 proB ALL and one unknown cases. The following drugs were tested: daunorubicin, doxorubicin, mitoxantrone, idarubicin (Ida), prednisolone (Pred), dexamethasone (DXM), vincristine (VCR), Asparaginase (Asp), 6-MP, 6-TG, AraC, VM26 and 4-HOO-ifosfamide (Ifos). Infants <1.5 years were significantly more resistant to Pred (>500-fold), Asp (11-fold) and VM26 (2.7-fold) but significantly more sensitive to Ara-C (2.3-fold) compared to the intermediate age group. When analyzing infants <1 year of age similar results were found. ProB ALL cells (seven infants <1.5 years; eight children >1.5 years) were significantly more resistant to glucocorticoids, Asp, thiopurines, anthracyclines and Ifos compared to cALL/preB ALL but more sensitive to Ara-C. Cells from children >10 years were significantly more resistant to Pred, DXM, Asp, Ida and 6-MP. T-ALL cells showed a strong resistance to Pred, Asp and VCR and a mild but significant resistance to all other drugs except thiopurines and VM26. We conclude that the poor prognosis of infant ALL is associated with a resistance to glucocorticoids and Asp. However, ALL cells from infants show a relatively high sensitivity to Ara-C which suggests that infants with ALL might benefit from treatment schedules that incorporate more Ara-C than the current treatment protocols.

Adolescent↗
PubMed1998

Mechanisms of cellular anthracycline resistance in childhood acute leukemia.

Cellular resistance to anthracyclines is often associated with an unfavorable clinical outcome in a variety of cancers, including leukemia. Several mechanisms of anthracycline resistance may be involved such as an impaired transport of drugs across the plasma membrane, an increased drug efflux, an increased intracellular detoxification of drugs, a reduced availability of intracellular drug targets, or a reduced ability of cells to induce apoptosis. Here, we review the studies published about mechanisms which may explain resistance to anthracyclines in leukemic cells of pediatric patients.

Acute Disease↗
PubMed1998

Ex vivo activity of methotrexate versus novel antifolate inhibitors of dihydrofolate reductase and thymidylate synthase against childhood leukemia cells.

Leukemic cells of 27 children [14 patients with initial acute lymphoblastic leukemia (iALL), 8 patients with relapsed ALL (rALL), and 5 patients with acute nonlymphoblastic leukemia (ANLL)] were evaluated for their sensitivity to methotrexate (MTX) and five novel antifolate drugs, which have the potential to circumvent MTX resistance. The novel antifolates include a polyglutamatable [edatrexate (EDX)] and a lipophilic (trimetrexate) inhibitor of dihydrofolate reductase and two polyglutamatable inhibitors (ZD1694 and GW1843U89) and one lipophilic inhibitor (AG337) of thymidylate synthase (TS). Drug activity was assessed via the determination of in situ inhibition of TS activity after exposing leukemic cells to antifolate drugs for: (a) 3 h, followed by a 15-h drug-free period; and (b) 18 h of continuous exposure. For human CEM leukemia cell lines with well-defined mechanisms of resistance to MTX, in situ TS inhibition correlated with the growth-inhibitory effects of MTX and the novel antifolates (r = 0.86-0.93; P < 0.01). Although a wide interpatient variability in MTX sensitivity was observed within the three leukemia groups, the median drug concentration required to inhibit TS activity to 50% of untreated controls (TSI50) for a 3-h exposure to MTX was similar for iALL and rALL cells but was up to 9-fold higher in ANLL cells. After a 3-h exposure, EDX, ZD1694, and GW1843U89 displayed a markedly (10-150-fold) increased potency over MTX in all leukemia groups with comparable TSI50 values for ANLL and iALL cells. Compared with a 3-h MTX exposure, continuous exposure resulted in lower TSI50 values for iALL (14-fold), rALL (14-fold), and ANLL cells (85-fold). In comparison to MTX, the TSI50 values in these groups were also lower for EDX (1.6-3.5-fold), ZD1694 (2.1-4.3-fold), and GW1843U89 (15-35-fold). On short-term exposure, the lipophilic drugs trimetrexate and AG337 displayed markedly less potency as compared with that of long-term exposure. In conclusion, the efficacy of novel antifolates against childhood leukemia cells can be tested with the in situ TS inhibition assay. These novel antifolates displayed a greater efficacy than MTX against childhood leukemia cells and may have potential for the circumvention of MTX resistance in ANLL cells.

Antimetabolites, Antineoplastic↗
PubMed1997

In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia.

As an important determinant of the response to chemotherapy, measurements of cellular drug resistance may provide prognostically significant information, which could be useful for optimal risk-group stratification. The objective of this report is to determine the relation between in vitro resistance to 12 drugs, measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and long-term clinical response to chemotherapy in 152 children with newly diagnosed acute lymphoblastic leukemia. At risk-group stratified analyses, in vitro resistance to prednisolone, L-asparaginase, and vincristine were each significantly (P < .01) related to the probability of disease-free survival (pDFS) after combination chemotherapy. The combination of data for prednisolone, L-asparaginase, and vincristine provided a drug-resistance profile with prognostic independent significance superior to that of any single drug or any other factor. The 3-years pDFS was 100% for the group with the most sensitive profile, 20% of all patients, 84% (SE 6%) for the group with an intermediately sensitive profile, 40% of all patients, and 43% (SE 8%) for the remaining group with the most resistant profile (P < .001). In conclusion, the extent of in vitro cellular resistance to prednisolone, L-asparaginase, and vincristine, measured using the MTT assay, was significantly related to the clinical response to combination chemotherapy. Treatment failure in newly diagnosed childhood ALL can be predicted based on cellular drug resistance data.

Adolescent↗
PubMed1997

The use of reporter antigens in the popliteal lymph node assay to assess immunomodulation by chemicals.

Various drugs and other chemicals can induce T-cell-dependent B-cell activation which may lead to allergic or autoimmune-like diseases. Because the nature of the relevant (neo-) antigens is generally not known and probably depends on the chemical, we have explored the potential use of reporter antigens to determine T-cell-dependent B-cell activation by chemicals. TNP-Ficoll and TNP-OVA were used for this purpose because they are recognized by the same TNP-specific B cells, but these cells require distinct costimulation for specific antibody production. It was found that HgCl2, phenytoin, nitrofurantoin, and D-penicillamine stimulated IgG1 production to both antigens, incomplete Freund's adjuvant, silica, and dimethylsulfoxide to TNP-OVA only, and LPS and hydroxyl-amino procainamide to TNP-Ficoll alone. The diabetogene streptozotocin did not enhance IgG1 production, but may enhance a cellular response instead. Tolerogens and a T-cell antigen without intrinsic adjuvant activity did not influence the responses. The IgG1 production to TNP-Ficoll was local and transient, and did not always require T cells. In contrast, responses to TNP-OVA could be measured in serum, led to specific memory, and were strictly T-cell dependent. These results demonstrate that specific antibody production to reporter antigens indicates immunostimulatory effects of chemicals more sensitive than PLN cell count and provides important mechanistic information. Moreover, with TNP-OVA as reporter antigen the kinetics and regulation of chemically enhanced immune responses can be studied without the need to know the relevant neo-antigens for each individual compound.

Adjuvants, Immunologic↗
PubMed1997

Organotin-induced apoptosis as observed in vitro is not relevant for induction of thymus atrophy at antiproliferative doses.

The organotin compounds di-n-butyltin dichloride (DBTC) and tri-n-butyltin chloride (TBTC) selectively cause thymus atrophy. Previously, DBTC and TBTC were shown to inhibit proliferation of immature thymocytes, but other studies demonstrated that TBTC but not DBTC increased apoptosis in vitro and also in vivo. In this study, we examined whether apoptosis is increased in vitro by DBTC and TBTC at various concentrations and periods of incubation and whether apoptosis is involved in the induction of thymus atrophy at selective antiproliferative doses. In vitro, DBTC or TBTC at a concentration of 3 microM significantly increased DNA fragmentation in freshly isolated rat thymocytes after preincubation for 10 min followed by a 22-hr culture period. After continuous exposure for 22 hr, apoptosis was observed to be optimum at 1 microM TBTC and 0.3 microM DBTC and lower or absent at higher concentrations. Apparently, apoptosis induced by organotins in vitro depends on both duration and concentration of exposure. Selective antiproliferative doses of DBTC nor TBTC increased apoptosis on day 1 or 2 after single oral exposure. In contrast, the corticosteroid dexamethasone caused a depletion of both small and large thymocytes and a marked increase of apoptosis on both days 1 and 2 after dosing. Thus, although apoptosis is involved in the in vitro cytotoxic effects of both organotin compounds, it seems not involved in thymus atrophy at a dose that selectively inhibits immature thymocyte proliferation.

Animals↗
PubMed1997

Optimal immunocytochemical and flow cytometric detection of P-gp, MRP and LRP in childhood acute lymphoblastic leukemia.

The clinical relevance of multidrug resistance (MDR)-related proteins in childhood acute lymphoblastic leukemia (ALL) is largely unknown. The diversity of techniques, fixation methods, storage of cells (fresh or cryopreserved) etc, may contribute to discrepancies observed between several studies. We therefore optimized the detection of P-glycoprotein (P-gp), MDR-associated protein (MRP) and lung resistance-related protein (LRP) by immunocytochemistry and flow cytometry in childhood ALL cells. Thirteen fixation methods were compared using six antibodies in both immunocytochemistry and flow cytometry. The optimal fixation for P-gp (C219, MRK16), MRP (MRPr1) and LRP (LRP56) was a mixture of 2% (v/v) formaldehyde solution and acetone incubated for only 10 s at room temperature (FAc). For MRP recognized by MRPm6, the optimal fixation condition was acetone for 5 min at room temperature in immunocytochemistry, and methanol for 15 min at -20 degrees C in flow cytometry. P-gp staining by 4E3 was strongly antibody batch-dependent; on cytospins FAc fixation was optimal, but inconclusive data were obtained by flow cytometry. The optimized fixation conditions on fresh samples revealed a day-to-day variation in staining (both increasing and decreasing) in one third of the immunocytochemical tests. In flow cytometry the day-to-day variation in the fluorescence index was -1 +/- 22%. In both techniques, staining was comparable between fresh and cryopreserved cells. We recommend the use of the above mentioned fixation methods in order to study the clinical relevance of P-gp, MRP and LRP in childhood ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia.

The Multidrug Resistance gene (MDR 1) is frequently expressed in acute myeloid leukaemia (AML). MDR 1 is associated with resistance to chemotherapy in vitro and with a poor response rate in AML. We have investigated the prognostic value of MDR 1 expression in relation to other patient characteristics with respect to response and survival. One hundred and thirty patients aged 0-88 years were treated for de novo AML with standard induction and consolidation chemotherapy. MDR 1 expression was determined by immunocytochemistry. Univariate and multivariate analyses were conducted to identify prognostic factors for reaching complete remission (CR) and for overall survival from diagnosis, in order to compare MDR 1 with known prognostic factors. Univariate analysis showed that higher MDR 1 expression was an adverse prognostic factor for CR (P<0.001), as was higher age (P<0.001) and unfavourable karyotype (P<0.01). These factors were also negative prognostic factors for overall survival (P<0.001, P<0.05 and P<0.005, respectively). In the multivariate analysis MDR 1 (P<0.001), higher age (P<0.001) and karyotype (P<0.01) were independent adverse prognostic factors for CR as well as for overall survival (P<0.001, P<0.005, P<0.001, respectively). Our data indicate that MDR 1 expression is a disease-related unfavourable prognostic factor which has a significant impact on complete remission and overall survival in AML. Analysis of MDR 1 may be used to determine prognosis in individual patients.

Acute Disease↗
PubMed1996

Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia.

It is generally assumed that prednisolone (PRD) and dexamethasone (DXM) have equal glucocorticoid activity of PRD is given at sevenfold higher doses. Results of clinical studies of childhood acute lymphoblastic leukemia (ALL) suggested that DXM is more potent relative to PRD than assumed. The purpose of this study was to determine the relative antileukemic activity of PRD phosphate and DXM phosphate in 133 untreated childhood ALL samples in vitro, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) assay. There was a marked variation in antileukemic activity of both agents among the patient samples. The median LC50 (drug concentration lethal to 50% of the ALL cells) for PRD phosphate was 3.50 microM, for DXM phosphate 0.20 microM. The individually calculated ratios of the LC50 values for PRD and DXM phosphate showed a large range from 0.7 to >500, with a median of 16.2. This 16-fold difference could not be explained by differences between these glucocorticoids in stability, hydrolysis into unesterified drug, adhesion to the wall of the microculture plates, or protein binding. ALL cells were cross-resistant to PRD and DXM phosphate (correlation coefficient = 0.85, P<0.000001). We conclude that the in vitro antileukemic activity of DXM phosphate is median 16-fold higher than that of PRD phosphate, which contrasts to the generally assumed factor of 7. Based on the higher potency of DXM, and its more favorable pharmacokinetics as reported in the literature, DXM may be preferred to PRD as the glucocorticoid in the treatment of ALL.

Adolescent↗
PubMed1996

Stress proteins (HSP) and chemical-induced autoimmunity.

Various environmental and iatrogenic chemicals have been implicated in the induction of autoimmune responses and biomarkers for identification of such chemicals are imperative. The present study was initiated to examine whether induction of stress protein (HSP) synthesis is a common effect of immunoactive chemicals. This would be interesting because HSP-induction could result in the presentation of HSP-derived T cell epitopes, and recognition of these epitopes by HSP-reactive T cells could facilitate the initiation of (auto)immune responses. Such a role for HSP would clarify early aspects of chemical induction of immune responses and could provide a valuable biomarker for the identification of potentially immunoactive chemicals. It was found that of eight immunoactive chemicals, only HgCl2, dinitrochlorobenzene, and dibutyltin dichloride induced synthesis of HSC73/HSP72 and HSP90 in murine splenocytes in vitro. The induction by HgCl2 was identical in splenocytes from mice susceptible or not for Hg-induced autoimmunity. Following footpad injection of HgCl2, but not diphenylhydantoin, a marginal induction of HSC73 and possibly HSP72 but not HSP90 was found to precede the chemical-induced lymphoproliferation in draining lymph nodes of BALB/c mice. Finally, using stimulation of the IgG1 response to TNP-ficoll as a model for non-antigen-linked, T cell-dependent B cell stimulation, it was found that stimulation of this response by chemicals is independent of HSP induction. From these results, we conclude that it is unlikely that HSP function as general initiating neoantigens in chemically induced autoimmune responses.

Animals↗
PubMed1996

In vitro resistance to cytosine arabinoside, not to daunorubicin, is associated with the risk of relapse in de novo acute myeloid leukaemia.

The efficacy of chemotherapy in acute myeloid leukaemia (AML) is limited by clinical drug resistance. We determined in vitro resistance to cytosine arabinoside (ARAC), daunorubicin (DNR), mitoxantrone (MITOX), m-amsacrine (AMSA) and etoposide (VP16) in 49 adults with de novo AML using the MTT assay. Results showed that nonresponders to chemotherapy were, in vitro, 2.9-fold more resistant to DNR, but not more resistant to ARA-C, compared to complete responders. However, complete responders who were in vitro resistant to ARA-C had a 4-fold higher risk of relapse (95% CI 1.3-12.5-fold) compared to complete responders in vitro sensitive to ARA-C. With a mean follow-up of 12 months the probability of continuous complete remission (CCR) for patients in vitro sensitive to ARA-C was 61% at 34 months (95% CI 28-82%), whereas all patients in vitro resistant to ARA-C relapsed within 18 months from diagnosis. This difference appeared to be independent of other clinical features such as sex, age, white blood cell count, FAB classification, and CD34 expression. In vitro resistance to DNR was not related to the probability of CCR. We conclude that in vitro drug resistance assessed with the MTT assay appears to be associated with short- and long-term clinical outcome in AML. Confirmatory studies comprising a sufficient number of patients for multivariate analyses should prove whether in vitro resistance to ARA-C will appear to be an independent risk factor.

Acute Disease↗
PubMed1996

The autoimmunogenic chemicals HgCl2 and diphenylhydantoin stimulate IgG production to TNP-Ficoll and TNP-OVA, supporting and extending the graft-versus-host hypothesis for chemical induction of autoimmunity.

Bypass of T-cell tolerance via non-cognate graft-versus-host (GVH)-like help from T-helper (Th) cells activated by chemically altered or induced epitopes, has been postulated as a mechanism underlying chemical induction of autoimmunity. To functionally test this hypothesis, we assessed whether the autoimmunogenic chemicals HgCl2 and diphenylhydantoin (DPH), like GVH reactions, stimulate specific immunoglobulin G (IgG) responses to trinitrophenyl (TNP)-Ficoll but not to TNP-ovalbumin. IgG responses were quantified in the popliteal lymph node by enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) assays 7 days after s.c. injection of antigens, parental cells, chemicals or combinations thereof into the footpad of semi-allogeneic F1 mice. Antigens, chemicals, or cells alone induced few TNP-specific IgG antibody-forming cell (AFC) compared with untreated mice. Co-injection of parental cells or chemicals with TNP-Ficoll stimulated the TNP-specific response per lymph node approximately 50- and approximately 40-fold, respectively. In contrast, the IgG response to TNP-ovalbumin could not be stimulated by GVH reactions, whereas HgCl2 and DPH dose-dependently increased this response up to approximately 25- and approximately 250-fold, respectively. However, responses to TNP-ovalbumin pre-incubated with HgCl2 or DPH could be stimulated approximately 6-8 fold by GVH reactions. Observed similar adjuvanticity of chemicals and parental cells for TNP-Ficoll support a GVH-like action of autoimmunogenic chemicals. In addition, the chemicals modify TNP-ovalbumin such that B cells recognizing this antigen become susceptible to non-cognate stimulation by GVH reactions.

Animals↗
PubMed1996

Short communication: Total craniofacial photon shell technique for radiotherapy of extensive angiosarcomas of the head.

Effective radiotherapy for extensive angiosarcomas of the face and scalp is technically difficult due to the complex shape of the volume at risk, which can consist of the superficial tissues of the entire head. This work reports the details of a rotational X-ray technique used to deliver a large part of the tumour dose. The technique consists of four consecutive 90 degree arcs with changing centre blocks to protect critical midline structures. Multilevel CT based treatment planning is carried out to determine the centre block dimensions and beam weights. As a result the radiation dose is delivered with acceptable uniformity over the entire shell of superficial tissues of the head. The overall treatment combines the rotational fields with large lateral field irradiation and/or local boosts with photons or electrons. Two of three patients treated with this technique had local control of the disease until their deaths at 13 and 18 months. A third patient responded well, with only a small region of stable disease at 9 months.

Aged↗
PubMed1996

Prognostic significance of peanut agglutinin binding in childhood acute lymphoblastic leukemia.

We previously reported the favorable prognosis associated with positive peanut agglutinin (PNA) binding in childhood T cell acute lymphoblastic leukemia (ALL), and hypothesized that this may be related to glucocorticoid sensitivity (Veerman et al. Cancer Res 1985, 45: 1890). The purposes of this prospective study involving 202 children with newly diagnosed ALL were to determine the relationship between PNA binding and (1) immunophenotype; (2) in vitro resistance to prednisolone (PRD) and dexamethasone and other drugs; (3) clinical response to a systemic PRD monotherapy (plus one intrathecal injection with methotrexate); and (4) multidrug chemotherapy. PNA positivity was more frequent in T cell ALL (65% of 43 cases) than in pro-B (0% of seven cases), common (17% of 106 cases) and pre-B (16% of 45 cases) ALL (P < 0.001). PNA binding was not associated with in vitro resistance to PRD or dexamethasone. However, in 38 evaluable T cell ALL patients, nine of 13 PNA-negative cases were clinically poor responders to PRD, while all 25 PNA-positive cases were good responders to PRD clinically (P < 0.0001). The four clinically poor PRD responders with B cell precursor (BCP)-ALL were also PNA negative. Within T cell ALL, PNA-positive patients had a 3.4-fold (95% Cl, 1.1-10.4, P = 0.03) lower relative risk of any event, than PNA-negative patients. Within BCP-ALL, PNA binding was not of prognostic significance. In conclusion, PNA positivity, especially frequent in T cell ALL, is a marker for a subgroup of childhood ALL patients who are very likely to respond well to systemic PRD 'monotherapy'. In addition, PNA positivity is a favorable prognostic factor in T cell ALL.

Adolescent↗
PubMed1995

In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia.

Cellular drug resistance is thought to be an important cause of the poor prognosis for children with relapsed or refractory acute lymphoblastic leukemia (ALL), but it is unknown when, to which drugs, and to what extent resistance is present. We determined in vitro resistance to 13 drugs with the MTT assay. Compared with 141 children with initial ALL, cells from 137 children with relapsed ALL were significantly more resistant to glucocorticoids, L-asparaginase, anthracyclines, and thiopurines, but not to vinca-alkaloids, cytarabine, ifosfamide, and epipodophyllotoxins. Relapsed ALL cells expressed the highest level of resistance to glucocorticoids, with a median level 357- and >24-fold more resistant to prednisolone and dexamethasone, respectively, than initial ALL cells, whereas the resistance ratios for the other drugs differed from 0.8- to 1.9-fold, intraindividual comparisons between initial and relapsed samples from 16 children with ALL showed that both de novo and acquired drug resistance were involved. Specific in vitro drug-resistance profiles were associated with high-risk relapsed ALL groups. In vitro drug resistance was also related to the clinical response to chemotherapy in relapsed/refractory childhood ALL. We conclude that drug resistance may explain the poor prognosis for children with relapsed/refractory ALL. These day may be helpful to design alternative treatment regimens for relapsed childhood ALL.

Antibiotics, Antineoplastic↗