Cytotoxic activity of topotecan in human tumour cell lines and primary cultures of human tumour cells from patients

Jonsson, Elin; Fridborg, H; Csòka, Katalin; Dhar, Sumeer; Sundström, Christer; Nygren, Peter; Larsson, Rolf

doi:10.1038/bjc.1997.364

Cited by 40 publications

(26 citation statements)

References 29 publications

(16 reference statements)

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“…CPT and its analogue CPT-11/SN38 are very poor substrates for the P170-glycoprotein (P-gp or MDR)-mediated transport and are not affected by the MRP. A reduced uptake of the drug unrelated to P-gp and MRP was found in ovarian cancer cell lines [44]. Independently of known resistance mechanisms, a cross-resistance of topo I inhibitors with mitoxantrone was observed [45].…”

Section: Resistance To Topo I Inhibitorsmentioning

confidence: 91%

Human DNA-Topoisomerases – Diagnostic and Therapeutic Implications for Cancer

Kellner

Rudolph²,

Parwaresch³

2000

Oncol Res Treat

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Topoisomerases constitute a family of highly conserved essential enzymes, which exist in all investigated living pro- and eukaryotic cells. They are indispensable for the control of DNA topology. Humans possess 4 types of topoisomerases, i. e. topoisomerase (topo) I, II, III and V. Topo I, a 100-kDa protein, is a member of the type-I enzyme group (type IB). Functionally, it is an ATP-independent DNA single-strand endonuclease and ligase that functions mainly during transcription but also during DNA replication. Topo II belongs to the type-II enzymes and is represented in humans by 2 highly homologous isoforms, α (170 kDa) and β (180 kDa). Contrary to topo I, the 2 topo II isoforms are ATP-dependent double-strand endonucleases and ligases. Topo I and the β-form of topo II are expressed in a proliferation-independent manner, whereas topo IIα is cell-cycle-regulated. Because of the crucial role of topoisomerases for the maintenance and replication of DNA during proliferation, cells become highly vulnerable when these functions are lost. Consequently, a wide range of drugs with cytostatic effects are topo inhibitors. Topo I inhibitors in clinical use belong to the camptothecin family, e. g. topotecan and irinotecan. Topo IIα inhibitors are constituents of most chemotherapeutic protocols and form a large heterogeneous group. It includes clinically used compounds such as the podophyllotoxin analogues etoposide and teniposide, the anthracyclines daunorubicin, doxorubicin and idarubicin, the anthracenedione mitoxantrone and amsacrine. Recently, substances with dual specificity that inhibit both topo I and topo IIα have been found. The clinical relevance of these new compounds remains to be established. Specific inhibitors of topo IIβ have not been described yet. The majority of topo inhibitors interfere with the religation step in the normal action of the enzymes, which leads to a stabilisation of the so-called cleavable complex. This results in DNA single-strand breaks in the case of topo I or double-strand breaks in the case of topo II. DNA single-strand breaks due to topo I inhibition are converted into double-strand breaks in the course of DNA replication. Such topo-mediated DNA strand breaks likely induce repair or apoptosis mechanisms via p53 and/or p21^WAF1/Clip1. As a consequence, while topoisomerases are required for proliferation, proliferation is also essential for efficacious topo inhibition. The cell-cycle-dependent expression of topo IIwas also successfully used for prognostic evaluations of survival in patients with cancer.

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Section: Resistance To Topo I Inhibitorsmentioning

confidence: 91%

Human DNA-Topoisomerases – Diagnostic and Therapeutic Implications for Cancer

Kellner

Rudolph²,

Parwaresch³

2000

Oncol Res Treat

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“…In addition, data from our laboratory showed that PAK-200S at non-cytotoxic concentrations significantly reversed MRP-mediated 250-fold resistance to doxorubicin in MRP-expressing human fibrosarcoma HT1080/Dr4 cells. Since recent data suggest that MRP may also confer resistance to topotecan in vitro (Jonsson et al, 1997;Jansen et al, 1998) and in vivo (U Vanhoefer et al, unpublished data), PAK-200S may have clinical advantages over other MDR-reversing agents (e.g. PSC-833), lacking significant inhibition of MRP-function (Twentyman et al, 1994;Vanhoefer et al, 1996).…”

Section: Top-i Dna Unwinding Activitymentioning

confidence: 99%

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

et al. 1999

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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.

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“…Activity was observed in sarcoma and childhood solid tumors demonstrating effectiveness even in cell lines expressing common mechanisms of cytostatic drug resistance such as p-glycoprotein (MDR) and glutathioneassociated resistance [12,13]. In addition, topotecan has also demonstrated activity against osteosarcoma xenografts, in particular when given as an oral formulation [14].…”

Section: Results Of Topotecan In Adult Soft-tissue Sarcomamentioning

confidence: 96%

“…In addition, topotecan has also demonstrated activity against osteosarcoma xenografts, in particular when given as an oral formulation [14]. Inhibition of cell lines derived from childhood sarcomas such as leiomyosarcoma and rhabdomyosarcoma has been demonstrated in vitro and in xenografted nude mouse models [12][13][14]. The Canadian Sarcoma Group has conducted a phase II study of topotecan given at the established schedule of 1.5 mg/m 2 per day for 5 consecutive days every 3 weeks in patients with previously untreated metastatic soft-tissue sarcomas.…”

Section: Results Of Topotecan In Adult Soft-tissue Sarcomamentioning

confidence: 99%

The Potential Role of Topotecan in the Treatment of Pediatric and Adult Soft-Tissue Sarcomas

Bokemeyer¹,

Kollmannsberger²,

Kanz³

1998

Oncol Res Treat

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Topotecan, a novel topoisomerase I inhibitor, has shown to be active in a variety of solid tumors. Studies have also investigated the potential role of topotecan in soft-tissue sarcomas. Sarcomas represent a heterogeneous group of neoplasms with more than 50 different histological subtypes. While soft-tissue sarcomas account for only 0.7% of all cancers in the adult, they are much more common in children. Current standard therapy consists of combined modality treatment including surgery followed by radiotherapy for localized diseases. In metastatic disease, combination chemotherapy with doxorubicin and ifosfamide, as the two most active agents, will achieve response rates in 25–35% of patients. However, no prolongation of survival has been achieved thus far as compared to doxorubicin monotherapy. Topotecan has shown to be active against sarcoma cell lines in vitro, even in cell lines expressing common mechanisms of resistance such as MDR. First results from clinical trials have indicated a limited activity with 10% response rates of topotecan when given as a 30-min infusion over 5 days. Based on several preclinical trials suggesting a higher activity of continuous infusion of topotecan, studies are underway examining the efficacy of this approach. Combination chemotherapy is an established therapy in children suffering from soft-tissue sarcomas. With a response rate of 46% in children with rhabdomyosarcoma, topotecan seems to be very effective against this disease. Therefore, studies are currently ongoing in order to compare topotecan to standard therapy and to evaluate topotecan as part of the established combination regimens. These results as well as further studies are clearly needed in order to define a potential role of topotecan in the treatment of adult and pediatric soft-tissue sarcomas.

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Cytotoxic activity of topotecan in human tumour cell lines and primary cultures of human tumour cells from patients

Cited by 40 publications

References 29 publications

Human DNA-Topoisomerases – Diagnostic and Therapeutic Implications for Cancer

Human DNA-Topoisomerases – Diagnostic and Therapeutic Implications for Cancer

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

The Potential Role of Topotecan in the Treatment of Pediatric and Adult Soft-Tissue Sarcomas

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