Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia.

Rowinsky, Eric K.; Adjei, Alex A.; Donehower, Ross C.; Gore, Steven D.; Jones, Richard J.; Burke, Philip J.; Cheng, Yung Chi; Grochow, Louise B.; Kaufmann, Scott H.

doi:10.1200/jco.1994.12.10.2193

Cited by 128 publications

(86 citation statements)

References 18 publications

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“…irinotecan and its active metabolite SN-38, TPT, 9-aminocamptothecin (9-AC) and GI-147211 (Sinha, 1995). These drugs show a broad spectrum of anti-cancer activity in preclinical and clinical studies (Giovanella et al, 1989;Rowinsky et al, 1992;Slichenmyer et al, 1993;Potmesil, 1994;Rowinsky et al, 1994;Tanizawa et al, 1994;Sinha, 1995;Conti et al, 1996). However, tumours may develop clinical resistance against these topo I inhibitors.…”

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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

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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.

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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

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“…In renal cell cancer (Ilson et al, 1993;Law et al, 1994) and colorectal cancer (Sugarman et al, 1994) the drug appears inactive. Little phase II experience has been reported for haematological tumours, although responses in phase I trials have been observed in patients with relapsed or refractory acute leukaemia (Kantarjian et al, 1993;Rowinsky et al, 1994).…”

Section: Resultsmentioning

confidence: 99%

“…Topo has shown clinical activity in many tumour types, for example ovarian carcinoma (Gore et al, 1996), NSCLC (PerezSolar et al, 1996) and leukaemia (Kantarjian et al, 1993;Rowinsky et al, 1994).…”

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confidence: 99%

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

Jonsson

Fridborg²,

Csòka³

et al. 1997

Br J Cancer

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Summary The cytotoxic activity and cross-resistance pattern of the novel topoisomerase inhibitor topotecan (Topo) were investigated in ten cell lines, representing different mechanisms of cytotoxic drug resistance, and in 218 fresh human tumour samples using the fluorometric microculture cytotoxicity assay (FMCA). Resistance to Topo in the cell lines was associated with expression of the multidrug resistanceassociated protein (MRP), whereas the cell lines with P-glycoprotein (P-gp), topoisomerase 11 and glutathione-associated resistance did not show decreased sensitivity to the drug. Topo was more active in haematological than in solid tumour samples, but substantial activity was observed in carcinomas of the ovary and breast, sarcoma and childhood solid tumours. Cross-resistance to standard drugs representing different mechanisms of action was generally low in patient cells. The effect of Topo was better after longer exposure, but this time-dependent effect was largely abolished when adjustment for in vitro exposure was made. Topo showed activity both in proliferative and non-proliferative cell systems. The results indicate that Topo is insensitive to major mechanisms of resistance except for MRP. Proliferation does not seem to be necessary for the effect of Topo, and no superiority for protracted dosing schedules was observed. The results also suggest that, for example, leukaemias, lymphomas, sarcomas and childhood solid tumours may be suitable targets for future phase 11 trials.

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“…Further studies on BTBD1 and BTBD2 are thus required to fill in the gaps concerning molecular events that regulate Topo1 activity, its involvement in vital biological functions such as mitosis and transcription, 3,[36][37][38] and in severe pathologies such as cancer and leukaemia. [15][16][17][18][19][20] Here we attempted to elucidate BTBD1 function in skeletal muscle, where this protein is mostly expressed.…”

Section: Discussionmentioning

confidence: 99%

“…It is therefore not surprising that repression or overexpression of the Topo1 gene can lead to cell death, [12][13][14] indicating that preservation of a normal level of Topo1 is crucial for cell survival. Moreover, Topo1 is more abundant in acute lymphocytic leukaemia and several human tumours than in normal tissue, [15][16][17][18][19][20] possibly because of a defect in its degradation, 21 and Topo1 inhibitors are used as antitumour agents. Although many proteins have been described as interacting with Topo1 to regulate its activity.…”

Section: Introductionmentioning

confidence: 99%

The topoisomerase 1-interacting protein BTBD1 is essential for muscle cell differentiation

et al. 2004

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DNA topoisomerase I (Topo1) contributes to vital biological functions, but its regulation is not clearly understood. The BTBD1 protein was recently cloned on the basis of its interaction with the core domain of Topo1 and is expressed particularly in skeletal muscle. To determine BTBD1 functions in this tissue, the in vitro model used was the C2C12 mouse muscle cell line, which expresses BTBD1 mainly after myotube differentiation. We studied the effects of a stably overexpressed BTBD1 protein truncated of the 108 N-terminal amino-acid residues and harbouring a C-terminal FLAG tag (D-BTBD1). The proliferation speed of D-BTBD1 C2C12 cells was significantly decreased and no myogenic differentiation was observed, although these cells maintained their capacity to enter adipocyte differentiation. These alterations could be related to Topo1 deregulation. This hypothesis is further supported by the decrease in nuclear Topo1 content in D-BTBTD1 proliferative C2C12 cells and the switch from the main peripheral nuclear localization of Topo1 to a mainly nuclear diffuse localization in D-BTBTD1 C2C12 cells. Finally, this study demonstrated that BTBD1 is essential for myogenic differentiation.

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Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia.

Abstract: These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT Css values are achievable, and that further developmental trials are warranted.

Cited by 128 publications

References 18 publications

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

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

The topoisomerase 1-interacting protein BTBD1 is essential for muscle cell differentiation

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