[131I]MIBG and topotecan: A rationale for combination therapy for neuroblastoma

Cancer Letters 228 (2005) 221–227 www.elsevier.com/locate/canlet

[131I]MIBG and topotecan: A rationale for combination therapy for neuroblastoma Anthony G. McCluskeya,*, Marie Boyda, Mark N. Gazeb, Robert J. Mairsa a

Targeted Therapy Group & Department of Child Health, Cancer Research UK Beatson Laboratories, University of Glasgow, Garscube Estate, Glasgow G61 1BD, UK b Middlesex Hospital, Mortimer Street, London, UK Received 27 October 2004; accepted 23 November 2004

Abstract MIBG is selectively concentrated in neuroblastoma cells, and radioiodinated MIBG has been used with some success for targeted radiotherapy. However, long-term cure remains elusive, and the topoisomerase I inhibitor topotecan may improve upon existing [131I]MIBG therapy. While synergistic killing by combinations of ionising radiation and topoisomerase I inhibitors has been reported, there is no consensus on optimal scheduling. Furthermore, there has been no attempt to demonstrate radiopotentiation by topoisomerase I inhibitors and targeted radiotherapy. We are investigating various scheduled combinations of topotecan and [131I]MIBG on neuroblastoma cells, and preliminary data suggests that topotecan induces increased accumulation of [131I]MIBG in vitro. q 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: [131I]MIBG; Topotecan; Targeted radiotherapy

1. Targeted radiotherapy for neuroblastoma Neuroblastoma, the most common extracranial solid tumour of childhood, has a long-term survival rate of only 15% [1]. It is a heterogeneous disease and, at presentation, 67% of neuroblastoma patients have metastases [2]. While patients with stages 1 and 2 disease can usually be treated surgically, without the need for radiotherapy and/or chemotherapy [2],

* Corresponding author. Tel.: C44 141 330 4129; fax: C44 141 330 4127. E-mail address: [email protected] (A. G. McCluskey).

patients with inoperable stages 3 and 4 (with the exception of patients with stage 4S, who generally display spontaneous regression without intensive intervention [2,3]), require intensive treatments, or ‘megatherapies’, involving combinations of highdose myeloablative chemotherapy with total body irradiation (TBI) and stem cell rescue [1,2]. However, despite the use of such aggressive therapies, in recent years there has been no substantial improvement in the survival rates of patients with advanced disease [4]. It has previously been established that neuroblastoma tumours are radiosensitive [5–7], and external beam irradiation has been used extensively in

0304-3835/$ - see front matter q 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2004.11.062

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the treatment of both localised and metastatic neuroblastoma tumours [8]. However, the maximum deliverable dose of whole body irradiation is limited by the intolerance of normal tissue. This problem can be overcome by targeted radiotherapy, where cytotoxic radionuclides are conjugated to tumour-seeking agents, leading to the selective irradiation of malignant foci, with the sparing of normal tissues [9]. The use of tumour targeting radiolabelled agents promises high tumour specificity and improved penetration without evoking an immune response [10]. Furthermore, while heterogeneous uptake of the radioactive agent can result only in a fraction of tumour cells being successfully targeted, energy released by decay of the radioisotope emanates from the targeted portion of the tumour in three dimensions, causing damage to neighbouring cells that have not accumulated the radiolabelled drug [11]. Therefore, even if the success rate of transfer of the radiolabelled agent to tumour cells is less than 100%, underdosing of the tumour is circumvented. Because neuroblastoma is a radiosensitive tumour, it is suitable for targeted radiotherapy, using [131I]MIBG. Meta-iodobenzylguanidine (MIBG), a derivative of the adrenergic neurone-blocking drugs bretylium and guanethidine, is a structural analogue of noradrenaline. 85–90% of neuroblastoma cells express the noradrenaline transporter (NAT), a 12-spanning integral membrane protein responsible for the active intracellular accumulation of catecholamine neurotransmitters [12,13]. MIBG is also selectively concentrated in neuroadrenergic tissue and NATexpressing tumours by this process [12,13], and tracer doses of radioiodinated MIBG have been used successfully for diagnostic scintigraphy of tumours derived from the neural crest [14]. It is expected that the ability of neural crest-derived tumours to accumulate and retain high concentrations of [131I]MIBG will lead to a therapeutic use for this drug [8]. Targeted therapy using [131I] MIBG has induced favourable remissions in some patients when used as a single agent [15–17]. However, long-term cure remains elusive, and the full potential of this therapy may only be realised when it is combined with other agents [18]. One such agent with the potential to improve [131I]MIBG therapy is the topoisomerase I inhibitor topotecan (TPT).

2. Topoisomerase I Topoisomerase I (Topo I) is a nuclear enzyme that relaxes supercoiled DNA and plays a crucial role in DNA replication and in transcription [19–21]. Topo I removes the topological tension in front of replication forks by inserting a nick on one of the DNA strands and allowing the other strand to pass through the cleavage site, before re-sealing the nick. During this process, an intermediate state is formed by transient covalent bonding between the tyrosine residues of the Topo I and the 3 0 termini of the nicked strand (the socalled ‘cleavable complex’) [20,21].

3. Inhibitors of topoisomerase I: camptothecin and topotecan Camptothecin (CPT), an alkaloid extract of the tree Camptotheca acuminata, was first identified in 1966 as exhibiting antitumour activity in murine leukemia models [20], although it was not until 1988 that the mode of action was identified as Topo I inhibition [22]. The hypothesised cytotoxic mechanism of camptothecin is known as the fork collision model. Briefly, CPT binds to, and stabilises the normally transient cleavable complex, inhibiting the Topo I-induced religation step. During the next round of DNA replication, collision of the stabilised Topo I–DNA complex with the replication fork results in an irreversible double strand break, leading to cell cycle arrest and cell death [20,23]. Clinical trials of CPT were carried out in 1970s. However, these were terminated due to excessive and unpredictable toxicity [20,23]. Instead, researchers attempted to synthesise derivatives of camptothecin which would exhibit lower toxicity and greater solubility in water. This led to the identification of a new class of campotothecin analogues, including the semi-synthetic derivative topotecan. Topotecan has been entered into clinical trials for neuroblastoma, and has shown effectiveness as a single agent in phase I/II trials [24–26]. Furthermore, when combined with other chemotherapeutic agents (for example, topotecan given in combination with cyclophosphamide in phase II trials [27], and topotecan given in combination with myeloablative doses of thiotepa and carboplatin [28]), encouraging

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results have been obtained. It is expected that the effectiveness of TPT against neuroblastoma could be greatly enhanced if this agent is given in combination with [131I]MIBG, due to the ability of TPT to potentiate radiation-induced toxicity.

4. Radiosensitisation by inhibitors of topoisomerase I Many previous studies have reported synergistic cell killing in vitro by ionising radiation and Topo I inhibitors in non-human cell lines [29,30] and in human cancer-derived cell lines [23,30–34]. In vivo radiopotentiation by Topo I inhibitors has also been observed [33,35,36]. The underlying mechanism of TPT radiopotentiation of cell death is, at present, unknown. Most theories concerning TPT-induced cell death rely on the fork collision model described above [23]. However, this model is predominantly S-phase specific, and does not explain enhanced TPT-induced cell death following irradiation. The specific role played by Topo I in the cellular response to DNA damage is, at present, unclear.

5. Topoisomerase I and DNA damage Following the formation of a number of different types of DNA lesions (e.g. single strand breaks, creation of apurinic sites, base-pair mismatches), nicked DNA acts as a substrate for Topo I, and there is a rapid sequestration of the enzyme onto the sites of DNA lesions [37–40]. While experimental evidence suggests that, following radiation-induced DNA damage, Topo I mRNA and protein levels remain unaffected, a down-regulation in the ability of Topo I to relax supercoiled DNA has been observed [41]. This suggests that any involvement that Topo I has in the repair of DNA damage does not involve its DNA cleavage/resealing activity. It is possible that inactive Topo I helps to stabilise the site of damage until the DNA repair pathway becomes involved [40,42]. Alternatively, the creation of a complex between inactive Topo I and DNA at the site of damage may act as a marker for DNA repair enzymes [40,42,43].

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Due to their ability to initiate DNA strand breakage and ligation events, Topo I–DNA complexes are potentially dangerous to the cell, and there is some evidence to suggest that a variety of DNA lesions, if located near a Topo I scissile site, can stimulate a Topo Imediated cleavage reaction, either on the scissile strand, or on the opposite strand [42]. This would exacerbate the effects of the original lesion by causing the formation of additional single strand breaks, irreparable double strand breaks, deleterious recombination events and covalent protein-DNA crosslinks. To prevent this, in normal circumstances the interacellular levels of Topo I are constant, and the number and duration of Topo I–DNA complexes are strictly controlled [43]. While the fork-collision model of TPT-induced cell death does not explain how this drug causes radiosensitisation, a more controversial theory has been proposed, which suggests that the effect of TPT on Topo I may be more potent. Boothman et al. (1994) suggested that the radiopotentiation exhibited by cells treated with camptothecin analogues may be due to enhanced Topo I-induced DNA cleavage activity [41]. In this alternative scenario, topotecan, by stabilising the Topo I–DNA complex, increases the probability of unintended Topo I-mediated cleavage reactions [41,43]. Therefore, following radiationinduced DNA damage, TPT-stabilised Topo I inappropriately cleaves either the damaged strand, multiplying the amount of single strand DNA breaks, or the intact strand opposite the initial lesion, converting a single strand break into a potentially lethal double strand break [41,42].

6. [131I]MIBG and topotecan combination therapy for neuroblastoma No attempt has been made to investigate the potential of inhibitors of topoisomerase I to induce radiopotentiation in vitro and in vivo when combined with targeted radiotherapy. While it is unclear whether a synergistic interaction will be observed if TPT is used in conjunction with [131I]MIBG, it has previously been reported that a wide range of DNAinteracting agents cause an increase in the ability of neuroblastoma cells to actively accumulate radiolabelled MIBG [44–47] (Table 1). Our preliminary results suggest that administration of TPT also

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Table 1 Effect of topotecan pretreatment on [131I]MIBG uptake: Comparison with other DNA interacting agents Treatment

[131I]MIBG uptake enhancement factor

5 Gy g-rays IFN-gCretinoic acid IFN-gCIFN-a Cisplatin Adriamycin Topotecan

1.8 3.0 2.5 2.8 3.0 2.5

Previous studies have shown that a wide range of agents which interact with DNA cause an enhancement in the ability of neuroblastoma cell lines to actively accumulate radiolabelled MIBG in vitro [44–47]. Administration of topotecan induces a similar enhancement of [131I]MIBG uptake (Fig. 1). This suggests that a common mechanism may be involved.

induces an increase in accumulation of [131I]MIBG in neuroblastoma cell lines (Fig. 1, Table 1). This suggests that, in addition to its direct toxic effect, administration of TPT could enhance the uptake of [131I]MIBG by neuroblastoma tumours, resulting in improved efficacy. Although synergistic cell killing in vitro and In vivo by ionising radiation and Topo I inhibitors have been

widely reported, there is no consensus with respect to the order of delivery of these therapeutic agents (Table 2). While some studies state that radiosensitisation is observed when Topo I inhibitors are administered prior to irradiation [23,33], others claim that radiopotentiation is only achieved when exposure to ionising radiation precedes, or is concurrent with administration of Topo I inhibitors [29,34]. The specific nature of the interaction between Topo I inhibitors and ionising radiation is unknown. Likewise, the nature of the interaction between camptothecins and targeted radiotherapy is unresolved, and it is possible that any synergistic effects resulting from a combination of TPT and [131I]MIBG may be affected by the scheduling of the two drugs. While our preliminary data shows that administration of TPT prior to [131I]MIBG exposure leads to an increase in uptake, it is possible that other factors may be involved in the cellular response to damage caused by these two agents, and this may not be the optimal order of administration for combination therapy. Therefore, investigations are underway to examine the potential of different scheduled combinations of

Fig. 1. The effect of topotecan on [131I]MIBG uptake. The effect of TPT pretreatment on the ability of neuroblastoma cells to accumulate [131I]MIBG was studied using a previously established protocol [44]. SK-N-BE(2c) and SHSY5Y cells were treated with TPT for 24 h, and then either assayed immediately, or left in fresh medium, and tested at 24 h intervals up to 72 h. Cells assayed immediately following TPT treatment exhibited little stimulation of [131I]MIBG uptake compared to untreated controls (C). However, cells that were incubated in fresh medium for 24 h, exhibited an enhanced ability to incorporate [131I]MIBG (approximately 2.5! that of untreated controls). Cells assayed at 48 h retained an increased ability to uptake [131I]MIBG. Cells tested 72 h after removal of TPT exhibited no increase in [131I]MIBG uptake compared to untreated controls. This pattern was observed in both cell lines tested.

A.G. McCluskey et al. / Cancer Letters 228 (2005) 221–227 Table 2 Scheduled combinations of ionising radiation and Topo I inhibitors reported to cause synergistic cell killing

In vitro non-human cell lines Murine leukemia (P388) Chinese hamster ovary (CHO) Chinese hamster fibroblast (V79) In vitro: human cell lines Breast cancer (MCF7) Cervical cancer (HeLa) Small-cell lung cancer (SBC3-CDDP) Glioblastoma (GBM) Squamous carcinoma of the head and neck (SCC-25) Melanoma (U1-Mel) In vivo models Murine fibrosarcoma Murine mammary carcinoma Human rhabdomyosarcoma

Treatment schedule examined

Reference

(iii), (iv), (v) (iii), (iv), (v)

[29] [29]

(iii)

[30]

(i), (iii), (v) (iii) (ii), (iii)

[23] [30] [31]

(ii), (iii), (iv) (i)

[31] [33]

(ii), (iii), (iv)

[34]

(i), (iii) (ii), (iii)

[33] [35]

(ii), (iii)

[36]

Synergistic cell killing by ionising radiation and Topo I inhibitors have been widely reported. However, there is no consensus on the order of delivery: (i) Synergy observed when Topo I inhibitors were administered prior to irradiation; (ii) Synergy observed when Topo I inhibitors were administered following irradiation; (iii) Synergy observed when Topo I inhibitors and radiation were administered concurrently; (iv) Administration of Topo I inhibitors prior to irradiation did not induce synergy; (v) Administration of Topo I inhibitors following irradiation did not induce synergy.

TPT and [131I]MIBG to alter the effectiveness of the combined treatment.

Acknowledgements This work was supported by the Neuroblastoma Society and Cancer Research UK.

References [1] S.H. Cunningham, R.J. Mairs, T.E. Wheldon, P.C. Welsh, G. Vaidyanathan, M.R. Zalutsky, Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions, Br. J. Cancer 77 (1998) 2061–2068.

225

[2] J.K. Simpson, M.N. Gaze, Current management of neuroblastoma, Oncologist 3 (1998) 253–262. [3] G.J. D’Angio, A.E. Evans, C.E. Koop, Special pattern of widespread neuroblastoma with a favourable prognosis, Lancet 1 (1971) 1046–1049. [4] S. Mastrangelo, A. Tornesello, L. Diociaiuti, A. Pession, A. Prete, V. Rufini, et al., Treatment of advanced neuroblastoma: feasibility and therapeautic potential of a novel approach combining 131I-MIBG and multiple drug chemotherapy, Br. J. Cancer 84 (4) (2001) 460–464. [5] N. Ohnuma, T. Kasuga, I. Najira, T. Furuse, Radiosensitivity of human neuroblastoma cell line (Nb-1), Gann 68 (1977) 711–712. [6] J.M. Deacon, P.A. Wilson, M.J. Peckham, The radiobiology of human neuroblastoma, Radiother. Oncol. 3 (1985) 201–209. [7] T.E. Wheldon, L. Wilson, A. Livingstone, J. Russell, J.A. O’Donaghue, A. Gregor, Radiation studies on multicellular tumour spheroids derived from human neuroblastoma: absence of sparing effects of dose fractionation, Eur. J. Cancer Clin. Oncol. 22 (1986) 563–566. [8] J.L. Habrand, G.J. D’Angio, Radiotherapy in neuroblastoma, in: G.M. Brodeur, T. Sawada, Y. Tsuchida, P.A. Vouˆte (Eds.), Neuroblastoma, Elsevier, Amsterdam, 2000, pp. 479–496. [9] R.J. Mairs, S.H. Cunningham, M. Boyd, S. Carlin, Applications of gene transfer to targeted radiotherapy, Curr. Pharm. Des. 6 (2000) 1419–1432. [10] K.K. Matthay, J.G. Villablanca, R.C. Seeger, D.O. Stram, R.E. Harris, N.K. Ramsay, et al., Treatment of high-risk neuroblastoma with chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid, N. Engl. J. Med. 341 (1999) 1165–1173. [11] R.J. Mairs, M. Boyd, Targeting radiotherapy to cancer by gene transfer, J. Biomed. Biotechnol. 2 (2003) 102–109. [12] S. Jacques, M.C. Tobes, J.C. Sissons, J.A. Baker, D.M. Wieland, Comparison of the sodium dependence of uptake of meta-iodo-benzylguanidine and norepenephrine into cultured bovine adrenomedullary cells, Mol. Pharmacol. 26 (1984) 539–546. [13] R.J. Mairs, A.L. Livingstone, M.N. Gaze, T.E. Wheldon, A. Barrett, Prediction of accumulation of 131I-meta-iodobenzylguanidine in neuroblastoma cell lines by means of reverse transcription and polymerase chain reaction, Br. J. Cancer 70 (1994) 97–101. [14] C.R. Staalman, C.A. Hoefnagel, Imaging of neuroblastoma and metastasis in: G.M. Brodeur, T. Sawada, Y. Tsuchida, P.A. Vouˆte (Eds.), Neuroblastoma, Elsevier, Amsterdam, 2000, pp. 303–332. [15] A. Garaventa, P. Guerra, A. Arrighini, L. Bertolazzi, M. Bestagno, B. De Bernardi, et al., Treatment of advanced neuroblastoma with [131I] metaiodobenzylguanidine, Cancer 67 (1991) 922–928. [16] P.A. Voute, C.A. Hoefnagel, J. de Kraker, R. Valdes Olmos, D.J. Bakker, A.J. Van Der Kleij, Results in treatment with [131I] metaiodobenzylguanidine in patients with neuroblastoma (Future Prospects of Zetotherapy, Advances in Neuroblastoma Research), 3rd ed, Wiley-Liss, New York, 1991. pp. 439–445.

226

A.G. McCluskey et al. / Cancer Letters 228 (2005) 221–227

[17] L.S. Lashford, I.J. Lewis, S.L. Fielding, Phase I/II study of iodine-131-metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom Children’s Cancer Study Group Investigation, J. Clin. Oncol. 10 (1992) 1889–1896. [18] R.J. Mairs, Neuroblastoma therapy using radiolabelled [131I] metaiodobenzylguanidine ([131I]MIBG) in combination with other agents, Eur. J. Cancer 35 (1999) 1171–1173. [19] S.J. Brill, S. DiNardo, K. Voelkel-Meiman, R. Sternglanz, Need for DNA topoisomerase I activity as a swivel for DNA replication for transcription of ribosomal RNA, Nature 326 (1987) 414–416. [20] M.L. Rothenberg, Topoisomerase I inhibitors: review and update, Ann. Oncol. 8 (1997) 837–855. [21] W. Voigt, S. Matsui, M.B. Yin, W.C. Burhans, H. Minderman, Y.M. Rustum, Topoisomerase I inhibitor SN-38 can induce DNA damage and chromosomal aberrations independent from DNA synthesis, Anticancer Res. 18 (1998) 3499–3506. [22] W.-K. Eng, L. Faucette, R.K. Johnson, R. Sternglanz, Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of campothecin, Mol. Pharmacol. 34 (1988) 755–760. [23] A.Y. Chen, H. Choy, M.L. Rothenberg, DNA topoisomerase I—targeting drugs as radiosensitizers, Oncology 13 (1999) 39–46. [24] C.B. Pratt, C. Stewart, V.M. Santana, L. Bowman, W. Furman, J. Ochs, et al., Phase I study of Topotecan for pediatric patients with malignant solid tumors, J. Clin. Oncol. 12 (1994) 539–543. [25] D.G. Tubergen, C.F. Stewart, C.B. Pratt, W.C. Zamboni, N. Winick, V.M. Santana, et al., Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of Topotecan using a five-day course in children with refractory solid tumors: a Pediatric Oncology Group Study, J. Pediatr. Hematol. Oncol. 18 (1996) 352–361. [26] A. Langler, A. Christaras, K. Abshagen, K. Krauth, B. Hero, F. Berthold, Topotecan in the treatment of refractory neuroblastoma and other malignant tumors in childhood—a phase-II-study, Klin. Padiatr. 214 (2002) 153–156. [27] R.L. Saylors, K.C. Stine, J. Sullivan, J.L. Kepner, D.A. Wall, M.L. Bernstein, et al., Cyclophosphamide plus Topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group Phase II Study, J. Clin. Oncol. 19 (2001) 3463–3469. [28] B.H. Kushner, N.-K.V. Cheung, K. Kramer, I.J. Dunkel, E. Calleja, F. Boulad, Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults, Bone Marrow Transplant. 28 (2001) 551–556. [29] M.R. Mattern, G.A. Hofmann, F.L. McCabe, R.K. Johnson, Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor Topotecan (SK&F 104864), Cancer Res. 51 (1991) 5813–5816. [30] C. Hennequin, N. Giocanti, J. Balosso, V. Favaudon, Interaction of ionising radiation with the topoisomerase I poison camptothecin in growing V-79 and HeLa cells, Cancer Res. 54 (1994) 1720–1728.

[31] H. Kohara, M. Tabata, K. Kiura, H. Ueoka, K. Kawata, M. Chikamori, et al., Synergistic effects of topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin, and irradiation in a cisplatin-resistant human small cell lung cancer cell line, Clin. Cancer Res. 8 (2002) 287–292. [32] R. Marchesini, A. Colombo, C. Caserini, P. Perego, R. Supino, G. Capranico, et al., Interaction of ionizing radiation with TPT in two human cell lines, Int. J. Cancer 66 (1996) 342–346. [33] R.E. Boscia, T. Korbut, S.A. Holden, G. Ara, B.A. Teicher, Interaction of topoisomerase I inhibitors with radiation in cisdiaminedichloroplatinum(II)- sensitive and -resistant cells in vitro and in the FSAIIC fibrosarcoma in vivo, Int. J. Cancer 53 (1993) 118–123. [34] J.P. Lamond, M. Wang, T.J. Kinsella, D.A. Boothman, Concentration and timing dependence enhancement between topotecan, a topoisomerase I inhibitor and ionising radiation, Int. J. Radiat. Oncol. Biol. Phys. 36 (1996) 361–368. [35] J.H. Kim, S.H. Kim, A. Kolozsvary, M.S. Khil, Potentiation of radiation response in human carcinoma cells in vitro and murine fibrosarcoma In vivo by topotecan, an inhibitor of DNA topoisomerase I, Int. J. Radiat. Oncol. Biol. Phys. 22 (1992) 515–518. [36] P. Chastagner, J.L. Merlin, C. Marchal, S. Hoffstetter, M. Barberi-heyob, G. Vassal, A. Duprez, In vivo potentiation of radiation response by topotecan in human rhabdomyosarcoma xenografted into nude mice, Clin. Cancer Res. 6 (2000) 3327–3333. [37] D.A. Boothman, D.K. Trask, A.B. Pardee, Inhibition of potentially lethal DNA damage repair in human tumour cells by b-lapachone, an activator of topoisomerase I, Cancer Res. 49 (1989) 605–612. [38] D.A. Boothman, A.B. Pardee, Inhibition of radiation-induced neoplastic transformation by b-lapachone, Proc. Natl Acad. Sci. USA 86 (1989) 4963–4967. [39] D.A. Boothman, M. Wang, R.A. Schea, H.L. Burrows, S. Strickfaden, J.K. Owens, Posttreatment exposure to camptothecin enhances the lethal effects of X-rays on radioresistant human malignant melanoma cells, Int J. Radiat. Oncol. Biol. Phys. 24 (1992) 939–948. [40] H.W. Thielmann, O. Popanda, H.J. Staab, Subnuclear distribution of DNA topoisomerase I and Bax protein in normal and Xeroderma pigmentosum fibroblasts after irradiation with UV light and g rays or treatment with topotecan, J. Clin. Res. Oncol. 125 (1999) 193–208. [41] D.A. Boothman, N. Fukunaga, M. Wang, Down-regulation of topisomerase I in mammalian cells following ionizing radiation, Cancer Res. 54 (1994) 4618–4626. [42] P.S. Kingma, N. Osheroff, The response of eukaryotic topoisomerases to DNA damage, Biochim. Biophys. Acta 1400 (1998) 223–232. [43] A.K. Larsen, C. Gobert, DNA topoisomerase I in oncology: Dr. Jekyll or Mr. Hyde?, Pathol. Oncol. Res. 5 (3) (1999) 171–178.

A.G. McCluskey et al. / Cancer Letters 228 (2005) 221–227 [44] A. Armour, S.H. Cunningham, M.N. Gaze, T.E. Wheldon, R.J. Mairs, The effect of cisplatin pretreatment on the accumulation of MIBG by neuroblastoma cells in vitro, Br. J. Cancer 75 (1997) 470–476. [45] P. Montaldo, L. Raffaghello, F. Guarnaccia, V. Pistoia, A. Garaventa, M. Ponzoni, Increase of meta-iodobenzylguanidine uptake and intracellular half-life during differentiation of human neuroblastoma cells, Int. J. Cancer 67 (1996) 95–100.

227

[46] D. Meco, A. Lasorella, A. Riccardi, T. Servidei, R. Mastrangelo, R. Riccardi, Influence of cisplatin and doxorubicin on 125I-metaiodobenzylguanidine uptake in human neuroblastoma cell lines, Eur. J. Cancer 35 (1999) 1227–1234. [47] L.A. Smets, M. Jannsen, M. Rutgers, K. Ritzen, C. Buitenhuis, Pharmacokinetics and intracellular distribution of the tumourtargetted radiopharmaceuticalm-iodo-benzylguanidine in SKN-SH neuroblastomas and PC-12 phaochromocytoma cells, Int. J. Cancer 48 (1991) 609–615.