High-performance liquid chromatographic analysis of the new antitumour drug SK&amp;F 104864-A (NSC 609699) in plasma

Beijnen, J. H.; Smith, Brian R.; Keijer, W.J.; Gijn, R. van; Huinink, W.W. ten Bokkel; Vlasveld, L Th; Rodenhuis, S.; Underberg, W.J.M.

doi:10.1016/0731-7085(90)80122-6

Cited by 90 publications

(39 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The concentration of TPT in the sample was measured using a previously described sensitive high-performance liquid chromatography (HPLC) method . Topo I inhibitors, such as TPT, exist in equilibrium between the lactone and the hydroxy-acid form (Beijnen et al, 1990), of which the lactone is the active form. The equilibrium between the TPT lactone and the hydroxy-acid form is pH dependent.…”

Section: P-gp and Mrp Expressionmentioning

confidence: 99%

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Maliepaard²,

Nooter³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary In order to unravel possible mechanisms of clinical resistance to topoisomerase inhibitors, we developed a topotecan-resistant human IGROV-1 ovarian cancer cell line, denoted IGROVTlOOr, by stepwise increased exposure to topotecan (TPT). The IGROVT100r cell line was 29-fold resistant to TPT and strongly cross-resistant to . However, the IGROVTlOOr showed only threefold resistance to camptothecin (CPT). Remarkably, this cell line was 32-fold resistant to mitoxantrone, whereas no significant cross-resistance against other cytostatic drugs was observed. No differences in topoisomerase protein levels and catalytic activity as well as topoisomerase cleavable complex stabilization by CPT in the IGROV-1 and IGROVTIOOr cell lines were observed, indicating that resistance in the IGROVTlOOr cell line was not related to topoisomerase I-related changes. However, resistance in the resistant IGROVTlOOr cell line to accompanied by decreased accumulation of the drugs to approximately 15% and 36% of that obtained in IGROV-1 respectively. No reduced accumulation was observed for CPT. Notably, accumulation of TPT in the IGROV-1 cell line decreased under energy-deprived conditions, whereas the accumulation in the IGROVTlOOr cell line increased under these energy-deprived conditions. The efflux of TPT at 370C was very rapid in the IGROV-1 as well as the IGROVT100r cell line, resulting in 90% efflux within 20 min. Importantly, the efflux rates of TPT in the IGROV-1 and IGROVTlOOr cell lines were not significantly different and were shown to be independent on P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP). These results strongly suggest that the resistance of the IGROVTlOOr cell line to TPT and SN-38 is mainly caused by reduced accumulation. The reduced accumulation appears to be mediated by a novel mechanism, probably related to impaired energy-dependent uptake of these topoisomerase drugs.

show abstract

Section: P-gp and Mrp Expressionmentioning

confidence: 99%

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Maliepaard²,

Nooter³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…Total topotecan was assayed as described by Beijnen et al (36). To convert topotecan carboxylate to lactone, 10 AL H 3 PO 4 was added to 200 AL plasma.…”

Section: Methodsmentioning

confidence: 99%

Phase I and Pharmacologic Study of Infusional Topotecan and Carboplatin in Relapsed and Refractory Acute Leukemia

Kaufmann¹,

Karp

Letendre

et al. 2005

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. Experimental Design: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. Results: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions,1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). Conclusions:The maximum tolerated dose was 1.6 mg/m 2 /d topotecan plus 150 mg/m 2 /d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.

show abstract

“…For the measurements of cellular topotecan concentrations, 1.0 µM topotecan was added for the indicated time. For reversed-phase high-performance liquid chromatography (RP-HPLC) analysis cells were centrifuged at 11 000  at 4°C, washed twice in ice-cold PBS buffer and resuspended in 500 µl of 0.1 M sodium citrate solution, and the extraction procedure was performed as described earlier (Beijnen et al, 1990). In brief, cells were lysed and deproteinized with 3 ml ice-cold methanol-acetonitrile (50:50, v/v), covered with nitrogen and frozen at -20°C for 12 h. After centrifugation at 1000  for 15 min, supernatants were evaporated in a Speed Vac Plus Concentrator (Savant Instruments Inc., Farmingdale, NY, USA), resuspended in 200 µl of the mobile phase (methanol-phosphate buffer [60:40, v/v] adjusted to pH 5.9), covered with nitrogen and stored at -20°C for a further 2 h. The samples were centrifuged (21 900  at 4°C for 5 min), and 50 µl of each sample were applied to HPLC.…”

Section: Rp-hplc-analysis Of Topotecan Concentrationsmentioning

confidence: 99%

Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

et al. 1999

View full text Add to dashboard Cite

Summary Recent data suggest that expression of the membrane P 170 -glycoprotein (P-gp) may confer resistance to the topoisomerase-I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 µM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function.

show abstract

High-performance liquid chromatographic analysis of the new antitumour drug SK&F 104864-A (NSC 609699) in plasma

Cited by 90 publications

References 1 publication

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Phase I and Pharmacologic Study of Infusional Topotecan and Carboplatin in Relapsed and Refractory Acute Leukemia

Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

Contact Info

Product

Resources

About