Effect of bevacizumab on intracranial meningiomas in patients with neurofibromatosis type 2 - a retrospective case series.

PURPOSE: The hallmark of neurofibromatosis type 2 (NF2) is bilateral vestibular schwannomas (VS). Approximately 80% of NF2 patients also have intracranial meningiomas. Vascular endothelial growth factor (VEGF) is expressed in both NF2-related and sporadic occurring meningiomas and anti-VEGF therapy (bevacizumab) may, therefore, be beneficial in NF2-related meningiomas. The purpose of the study was to report the effect of bevacizumab on meningiomas in NF2 patients. MATERIALS AND METHODS: We retrospectively reviewed the effect of bevacizumab on the cross-sectional area (CSA) of 14 intracranial meningiomas in 7 NF2 patients. Bevacizumab 10 mg/kg was administered intravenously every two weeks for six months and 15 mg/kg every three weeks thereafter. Patients were evaluated according to the modified Macdonald criteria with repeated magnetic resonance (MR) scans. RESULTS: The median duration of therapy was 27 months (range 16-34) and 42 MR scans (median 8, range 4-11) were reviewed. The median annual change in meningioma CSA prior to bevacizumab was 2% (range -4%-+76%). During treatment, a decrease in meningioma CSA was observed in 5 of 14 meningiomas (36%) in 5 of 7 patients (71%). The median decrease in CSA was -10% (range -3%--25%). One meningioma (7%) progressed and the remaining (93%) had stable disease. CONCLUSIONS: Bevacizumab may slow or reverse the growth of some NF-related meningiomas. However, we have previously reported a fatal case of intracerebral hemorrhage following bevacizumab in NF2 patients, wherefore, this effect needs to be balanced carefully against the risk of side effects.

The effect of bevacizumab on vestibular schwannoma tumour size and hearing in patients with neurofibromatosis type 2.

The hallmark of neurofibromatosis type 2 (NF2) is bilateral vestibular schwannomas (VS) and severe hearing loss is common in NF2 patients. Vascular endothelial growth factor (VEGF) expression level in NF2 correlates with tumour growth rate and bevacizumab, a VEGF-binding antibody, has previously been shown to induce tumour shrinkage and improve hearing. We retrospectively reviewed the effect of bevacizumab on hearing and VS tumour size in 12 consecutive NF2 patients. Bevacizumab 10 mg/kg was administered intravenously every second week for 6 months; hereafter, bevacizumab 15 mg/kg was administered every third week. Patients were evaluated with repeated audiometries, MR scans and clinical evaluations. Radiological response was defined as a 20 % or greater reduction in VS volume. A total of 398 treatments (median 36) were administered and the median duration on therapy was 22 months (range 7-34). We observed a radiological response (≥20 % tumour shrinkage) in seven out of 18 tumours (39 %) in six out of 12 patients (50 %). Sustained radiological responses were maintained in six tumours (33 %) for more than 2 months. Three patients had objectively improved hearing and five patients reported subjective benefit in neurological symptoms, including improved hearing. Toxicity was in general manageable; however, one patient died from cerebral haemorrhage which was possibly related to therapy. In conclusion, bevacizumab improved hearing and reduced the size of VS in some patients with progressive NF2 which corroborates previous findings; however, the risk of severe side effects should be carefully considered and discussed with the patients prior to treatment.

Dexrazoxane protects against myelosuppression from the DNA cleavage-enhancing drugs etoposide and daunorubicin but not doxorubicin.

PURPOSE: The anthracyclines daunorubicin and doxorubicin and the epipodophyllotoxin etoposide are potent DNA cleavage-enhancing drugs that are widely used in clinical oncology; however, myelosuppression and cardiac toxicity limit their use. Dexrazoxane (ICRF-187) is recommended for protection against anthracycline-induced cardiotoxicity. EXPERIMENTAL DESIGN: Because of their widespread use, the hematologic toxicity following coadministration of dexrazoxane and these three structurally different DNA cleavage enhancers was investigated: Sensitivity of human and murine blood progenitor cells to etoposide, daunorubicin, and doxorubicin +/- dexrazoxane was determined in granulocyte-macrophage colony forming assays. Likewise, in vivo, B6D2F1 mice were treated with etoposide, daunorubicin, and doxorubicin, with or without dexrazoxane over a wide range of doses: posttreatment, a full hematologic evaluation was done. RESULTS: Nontoxic doses of dexrazoxane reduced myelosuppression and weight loss from daunorubicin and etoposide in mice and antagonized their antiproliferative effects in the colony assay; however, dexrazoxane neither reduced myelosuppression, weight loss, nor the in vitro cytotoxicity from doxorubicin. CONCLUSION: Although our findings support the observation that dexrazoxane reduces neither hematologic activity nor antitumor activity from doxorubicin clinically, the potent antagonism of daunorubicin activity raises concern; a possible interference with anticancer efficacy certainly would call for renewed attention. Our data also suggest that significant etoposide dose escalation is perhaps possible by the use of dexrazoxane. Clinical trials in patients with brain metastases combining dexrazoxane and high doses of etoposide is ongoing with the aim of improving efficacy without aggravating hematologic toxicity. If successful, this represents an exciting mechanism for pharmacologic regulation of side effects from cytotoxic chemotherapy.

Combining etoposide and dexrazoxane synergizes with radiotherapy and improves survival in mice with central nervous system tumors.

PURPOSE: The treatment of patients with brain metastases is presently ineffective, but cerebral chemoradiotherapy using radiosensitizing agents seems promising. Etoposide targets topoisomerase II, resulting in lethal DNA breaks; such lesions may increase the effect of irradiation, which also depends on DNA damage. Coadministration of the topoisomerase II catalytic inhibitor dexrazoxane in mice allows for more than 3-fold higher dosing of etoposide. We hypothesized that dexrazoxane combined with escalated etoposide doses might improve the efficacy of cerebral radiotherapy. EXPERIMENTAL DESIGN: Mice with cerebrally inoculated Ehrlich ascites tumor (EHR2) cells were treated with combinations of etoposide + dexrazoxane + cerebral radiotherapy. Similar chemotherapy and radiation combinations were investigated by clonogenic assays using EHR2 cells, and by DNA double-strand break assay through quantification of phosphorylated histone H2AX (gammaH2AX). RESULTS: Escalated etoposide dosing (90 mg/kg) combined with dexrazoxane (125 mg/kg) and cerebral radiotherapy (10 Gy x 1) increased the median survival by 60% (P = 0.001) without increased toxicity, suggesting that escalated etoposide levels may indeed represent a new strategy for improving radiotherapy. Interestingly, 125 mg/kg dexrazoxane combined with normal etoposide doses (34 mg/kg) also increased survival from radiotherapy, but only by 27% (P = 0.002). This indicates a direct dexrazoxane modulation of the combined effects of etoposide and radiation in brain tumors. Further, in vitro, concurrent dexrazoxane, etoposide, and irradiation significantly increased DNA double-strand breaks. CONCLUSION: Combining etoposide (high or normal doses) and dexrazoxane synergizes with cerebral radiotherapy and significantly improves survival in mice with central nervous system tumors. This regimen may thus improve radiation therapy of central nervous system tumors.

Indication of a role of plasminogen activator inhibitor type I in protecting murine fibrosarcoma cells against apoptosis.

In a number of cancer types high tumor tissue levels of plasminogen activator inhibitor type 1 (PAI-1) protein are strongly associated with shorter cancer patient survival. This association has been intriguing since PAI-1 is known to inhibit urokinase plasminogen activator (uPA) that converts plasminogen to plasmin, which is actively involved in tumor progression and invasion. In order to further explore the biological role of PAI-1 in cancer, we have prepared fibroblasts from PAI-1 gene deficient mice and from their wild type littermates. From these fibroblasts fibrosarcoma cell lines were established and characterized. Both types of fibroblasts underwent spontaneous transformation as indicated by aneuploidy, immortalization, clonogenicity in soft agar and tumor formation in vivo. While both PAI-1 deficient and PAI-1 expressing cell lines showed similar proliferation rates in vitro, cells devoid of PAI-1 were significantly more sensitive to apoptotic stimuli. When inoculated subcutaneously into nude mice PAI-1 expressing cells rapidly established tumors, while PAI-1 deficient cells had a significantly longer lag-phase before they started to grow (p<0.0001). The present study suggests that PAI-1, besides its uPA inhibiting function, has a role in cancer progression by protecting tumor cells from undergoing apoptosis.

Metabolism of dexrazoxane (ICRF-187) used as a rescue agent in cancer patients treated with high-dose etoposide.

PURPOSE: The study was undertaken to determine the metabolism of dexrazoxane (ICRF-187) to its one-ring open hydrolysis products and its two-rings opened metal-chelating product ADR-925 in cancer patients with brain metastases treated with high-dose etoposide. In this phase I/II trial dexrazoxane was used as a rescue agent to reduce the extracerebral toxicity of etoposide. METHODS: Dexrazoxane and its one-ring open hydrolysis products were determined by HPLC and ADR-925 was determined by a fluorescence flow injection assay. RESULTS: The two one-ring open hydrolysis intermediates of dexrazoxane appeared in the plasma at low levels upon completion of dexrazoxane infusion and then rapidly decreased with half-lives of 0.6 and 2.5 h. A plasma concentration of 10 micro M ADR-925 was also detected at the completion of the dexrazoxane i.v. infusion period, indicating that dexrazoxane was rapidly metabolized in vivo. A plateau level of 30 micro M ADR-925 was maintained for 4 h and then slowly decreased. The pharmacokinetics of dexrazoxane were found to be similar to other reported data in other settings and at lower doses. CONCLUSIONS: The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These results suggest that the dexrazoxane intermediates are enzymatically metabolized to ADR-925 and provide a pharmacodynamic basis for the antioxidant cardioprotective activity of dexrazoxane.

Pharmacokinetics of etoposide in cancer patients treated with high-dose etoposide and with dexrazoxane (ICRF-187) as a rescue agent.

PURPOSE: The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide. METHODS: Etoposide plasma levels were determined by HPLC. RESULTS: The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses. CONCLUSIONS: The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.

A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIalpha in vivo.

The bisdioxopiperazines such as (+)-(S)-4,4'-propylenedi-2,6-piperazinedione (dexrazoxane; ICRF-187), 1,2-bis(3,5-dioxopiperazin-1-yl)ethane (ICRF-154), and 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione (ICRF-193) are agents that inhibit eukaryotic topoisomerase II, whereas their ring-opened hydrolysis products are strong iron chelator. The clinically approved analog ICRF-187 is a pharmacological modulator of topoisomerase II poisons such as etoposide in preclinical animal models. ICRF-187 is also used to protect against anthracycline-induced cardiomyopathy and has recently been approved as an antidote for alleviating tissue damage and necrosis after accidental anthracycline extravasation. This dual modality of bisdioxopiperazines, including ICRF-187, raises the question of whether their pharmacological in vivo effects are mediated through interaction with topoisomerase II or via their intracellular iron chelating activity. In an attempt to distinguish between these possibilities, we here present a transgenic mouse model aimed at identifying the contribution of topoisomerase IIalpha to the effects of bisdioxopiperazines. A tyrosine 165 to serine mutation (Y165S) in topoisomerase IIalpha, demonstrated previously to render the human ortholog of this enzyme highly resistant toward bisdioxopiperazines, was introduced at the TOP2A locus in mouse embryonic stem cells by targeted homologous recombination. These cells were used for the generation of transgenic TOP2A(Y165S/+) mice, which were demonstrated to be resistant toward the general toxicity of both ICRF-187 and ICRF-193. Hematological measurements indicate that this is most likely caused by a decreased ability of these agents to induce myelosuppression in TOP2A(Y165S/+) mice, highlighting the role of topoisomerase IIalpha in this process. The biological and pharmacological implications of these findings are discussed, and areas for further investigations are proposed.