In Vitro Chemopurification of Neuroblastoma Cells: Comparison of 6-Hydroxydopamine and Ascorbic Acid with 4-Hydroperoxycyclophosphamide

Sc, Gulati; Jh, Kwon; Kushner, Brian H.; Nk, Cheung; Atzpodien, Jens; Shum, KT; Clarkson, BD

doi:10.3109/07357908909041372

Cancer Investigation

1989

DOI: 10.3109/07357908909041372

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In Vitro Chemopurification of Neuroblastoma Cells: Comparison of 6-Hydroxydopamine and Ascorbic Acid with 4-Hydroperoxycyclophosphamide

Gulati Sc

Kwon Jh²,

Brian H. Kushner³

et al.

Abstract: To develop an effective neuroblastoma (NB) purging condition, we have compared in vitro cytotoxicity of 6-hydroxydopamine (6-OHDA) and ascorbic acid, with 4-hydroperoxycyclophosphamide (4-HC) on three NB cell lines (SK-N-BE2, SMS-SAN, and LA-N-1) and also upon human hematopoietic stem cells. Our study included mixing NB cells with 20-fold excess of irradiated bone marrow buffy coat cells to simulate the borderline remission marrow. When NB cells were treated without marrow cells, all three NB cell lines were v… Show more

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Cited by 5 publications

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High-dose melphalan with 6-hydroxydopamine–purged autologous bone marrow transplantation for poor-risk neuroblastoma

Kushner

Kwon

O’Reilly

et al. 1991

Cancer

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Long-term results are presented of 28 patients who were diagnosed with neuroblastoma at more than 12 months of age and who received melphalan 180 mg/m2 (n = 6) or 240 mg/m2 (n = 22) to consolidate remissions of Stage IV disease or to control refractory disease. Twenty-four patients also received dianhydrogalactitol 180 to 240 mg/m2, and 11 received total body irradiation 450 to 600 cGy. Autologous bone marrow transplantation (ABMT) was performed with marrow that was unpurged (n = 2) or purged ex vivo (n = 26) with 6-hydroxydopamine (6-OHDA) 20 micrograms/ml plus ascorbate 200 micrograms/ml. The median time to an absolute neutrophil count of 500/microliters was 21 days and to self-sustaining platelet counts more than 20,000/microliters, 28 days. One patient required infusion of unpurged reserve marrow. Two groups of patients underwent ABMT: (1) 17 patients (Group I) who were in first remission a median of 7 months after diagnosis; and (2) 11 patients (Group II) who had refractory disease or were in second remission. For Group I, event-free survival was 29% at 12 months and 6% at 24 months post-ABMT. All Group II patients died of disease or ABMT-related toxicity. Overall, of the 28 patients, one is a long-term relapse-free survivor; five died of ABMT-related toxicity; ten patients with tumors present at ABMT had progressive disease within 6 months of ABMT; and 12 patients with no measurable disease at ABMT relapsed 4 to 32 months (median, 12) post-ABMT. Among the latter, six relapses involved the primary site, and six were restricted to distant sites. These results--in accord with the long-term outcome in other series--suggest that for neuroblastoma high-dose melphalan cannot be relied on to ablate residual disease or to salvage patients with refractory tumors. In addition, the pattern of relapse in several patients could be explained by infusion of incompletely purged autografts; this would support recent laboratory evidence that 6-OHDA/ascorbate is a suboptimal purging method.

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High-dose melphalan with 6-hydroxydopamine–purged autologous bone marrow transplantation for poor-risk neuroblastoma

Kushner

Kwon

O’Reilly

et al. 1991

Cancer

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Autografting with bone marrow exposed to multiple courses of very high dose cyclophosphamide in vivo and to 4‐hydroperoxycyclophosphamide in vitro

Kushner

Gulati

O’Reilly

et al. 1990

Med. Pediatr. Oncol.

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Intensive chemotherapy prior to harvesting autologous bone marrow may be advantageous for cancers that infiltrate the bone marrow. This approach, however, may deplete hemopoietic reserves or damage the hemopoietic microenvironment and thereby jeopardize posttransplant engraftment; in vitro treatment of bone marrow to ensure a tumor-free state may enhance the risk of nonengraftment. We addressed these concerns in a pilot study of patients with disseminated neuroblastoma. Bone marrow was harvested after initial intensive therapy that included 1) three to six courses of very high dose cyclophosphamide (CPM) (100-140 mg/kg in five patients, 140-160 mg/kg in nine patients), plus doxorubicin and vincristine, followed by 2) a median of three strongly myelosuppressive courses of cisplatin/VP16. The median interval between courses was 23 days. The marrow was treated in vitro with the CPM congener 4-hydroperoxycyclophosphamide (4-HC) and cryopreserved. It was infused after a massive cytoreduction regimen of melphalan 180 mg/m2 (n = 7) or thiotepa 900 mg/m2 (n = 7), plus cisplatin, BCNU, VP16, and local radiation. All 14 patients reconstituted hemopoiesis (median of 37 days to neutrophils greater than or equal to 500/microliter and of 63 days to platelets greater than 50,000/microliters). The number per kilogram body weight of hemopoietic progenitor cells (CFU-GM, BFU-E) in the autografts correlated significantly with the rate of hematologic recovery. Preharvest CPM dosage, however, did not. The use of thiotepa, as opposed to melphalan, was associated with a significantly slower posttransplant platelet recovery, suggesting a possible adverse effect of high-dose thiotepa on posttransplant hemopoiesis. In sum, while reinforcing evidence of a stem cell sparing effect of CPM, this pilot study more importantly delineates the degree to which high-dose alkylator therapy can be exploited to attain maximal dose intensity beginning at diagnosis. This aggressive treatment approach may have wide applicability, since CPM is among the most active agents against a spectrum of pediatric cancers.

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Autologous bone marrow transplantation

Yahalom

Portlock²

1991

Current Problems in Cancer

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In Vitro Chemopurification of Neuroblastoma Cells: Comparison of 6-Hydroxydopamine and Ascorbic Acid with 4-Hydroperoxycyclophosphamide

Cited by 5 publications

References 15 publications

High-dose melphalan with 6-hydroxydopamine–purged autologous bone marrow transplantation for poor-risk neuroblastoma

High-dose melphalan with 6-hydroxydopamine–purged autologous bone marrow transplantation for poor-risk neuroblastoma

Autografting with bone marrow exposed to multiple courses of very high dose cyclophosphamide in vivo and to 4‐hydroperoxycyclophosphamide in vitro

Autologous bone marrow transplantation

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