Enhanced Tumor Uptake of Carboplatin and Survival in Glioma-bearing Rats by Intracarotid Infusion of Bradykinin Analog, RMP-7

Matsukado, Koichiro; Inamura, Takanori; Nakano, Shin; Fukui, Masashi; Bartus, Raymond T.; Black, Keith L.

doi:10.1097/00006123-199607000-00025

Cited by 149 publications

(73 citation statements)

References 39 publications

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“…The pattern of viral delivery noted here, combined with the HSV-tk/GCV bystander activity, should help eradicate locally invasive tumor or micrometastases distal from the main tumor mass. RMP-7, like other vasoactive agents such as BK, histamine, and leukotrienes, 21,22,27,35 can selectively open the BTB by increasing the permeability of brain tumor capillaries, which are morphologically different from normal brain capillaries. RMP-7 has been used previously to enhance the delivery of chemotherapeutic agents to brain tumors and is approved for human use.…”

Section: Discussionmentioning

confidence: 99%

“…This result is probably not surprising given the large load of virus that was injected and the somewhat leaky nature of the BTB itself. 26,27 Clearly, however, intracarotid infusion of RMP-7 augmented the delivery of virus to experimental brain tumors without increasing the amount of virus delivered to the normal brain. Importantly, disruption of the BTB using RMP-7 promotes vector uptake into the infiltrating edge of brain tumors, which is an area that is difficult to distinguish from the normal brain by the conventional treatment modalities of surgery, chemotherapy, or radiation.…”

Section: Discussionmentioning

confidence: 99%

“…26 For example, intracarotid administration of RMP-7 enhanced the tumorspecific delivery of carboplatin when administered either intra-arterially or intravascularly and improved survival in a rat glioma model. 27 Recently, this therapeutic paradigm (intravascular delivery of carboplatin with RMP-7) has been introduced in phase I and II clinical trials. 28 -29 Here we demonstrate that intra-arterial infusion of RMP-7 significantly enhances the delivery of a herpes virus vector bearing the HSV-tk and lacZ genes to intracranial rat 9 L gliosarcomas, with virtually no infection of the normal brain and minimal infection of peripheral tissue.…”

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Selective delivery of herpes virus vectors to experimental brain tumors using RMP-7

et al. 1999

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RMP-7, a bradykinin analog, has been shown to selectively open the blood-tumor barrier for the delivery of chemotherapeutic drugs to brain tumors. In contrast to bradykinin, RMP-7 has no hypotensive effects and has been approved for human use. This study was initiated to determine whether RMP-7 would open the blood-tumor barrier to virus vectors encoding tumor-killing genes in an experimental model. The herpes virus vector used, hrR3, which encodes virus thymidine kinase gene and the lacZ reporter gene, is defective in a gene encoding ribonucleotide reductase, replicates selectively in dividing tumor cells and not in postmitotic neural cells. It was determined that an optimum dose of RMP-7 (1.5-3.0 g/kg over 10 -15 minutes) enhanced viral delivery to brain tumors in rats bearing intracranial 9 L gliosarcomas when infused through the carotid artery immediately prior to virus vector application. Maximum expression of the lacZ reporter gene occurred at 3 days after intracarotid infusion. By 8 days, transgene expression was largely confined to tumor foci away from the main tumor mass. Viral delivery was essentially specific to tumor cells, with little transgene expression elsewhere in the brain. Minimal uptake and pathology was noted in the kidney, spleen, and liver. These findings indicate that intracarotid delivery of RMP-7 can augment the selective delivery of virus vectors to brain tumors in an experimental rat model, with the potential for application to human brain tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Selective delivery of herpes virus vectors to experimental brain tumors using RMP-7

et al. 1999

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“…Testing in animal models of glioma Elliott et al, 1996aElliott et al, , 1996bElliott et al, , 1996cMatsukado et al, 1996Matsukado et al, , 1998, as well as imaging studies in glioma patients (Warkne et al, 1995;Ford et al, 1996;Black et al, 1997) have demonstrated that Cereport not only increases permeability of the vasculature supplying brain tumours, but does so selectively. That is, the increased permeability is approximately 10-20 times greater in brain areas associated with tumours, as compared to normal, nontumour brain .…”

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Enhanced delivery of carboplatin into brain tumours with intravenous CereportTM (RMP-7): dramatic differences and insight gained from dosing parameters

et al. 1999

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Summary Cereport TM (RMP-7) is a selective bradykinin B2 receptor agonist which increases the permeability of the 'blood-brain tumour barrier' (BBTB) to increase delivery of chemotherapeutic agents to brain tumours. A series of experiments was performed in an RG2 rodent model of glioma to evaluate and refine intravenous (i.v.) parameters to optimize Cereport's clinical utility. The first experiment demonstrated that while carboplatin levels were increased by twofold when given as a bolus during the Cereport infusion, no increase in carboplatin levels were seen when Cereport and carboplatin were simultaneously co-infused for 15 min. A subsequent experiment established that a major factor responsible for the lack of an effect with the co-infusion paradigm was tachyphylaxis to Cereport during the 15 min infusion, for a progressively diminished response to Cereport occurred over that time frame, as plasma levels of carboplatin were rising. A final experiment adjusted the timing of the Cereport and carboplatin infusions so that higher plasma carboplatin levels were achieved prior to initiating the Cereport infusion. Significant uptake effects were achieved when the carboplatin infusion preceded the Cereport infusion by 10 min (i.e. 5 min overlap in the delivery of the two agents). Collectively, these data provide the first systematic evaluation of dosing parameters involving receptor-mediated changes in BBTB permeability and provide new information regarding the pharmacodynamics and potential clinical use of Cereport.

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“…More recently, bradykinin (Black, 1995;Matsukado et al, 1998;Nomura et al, 1994) and the bradykinin agonist Cereport ® (RMP-7) (Bartus et al, 1996a, b;Doctrow et al, 1994;Straub et al, 1994) have been used to stimulate the receptors on the endothelial cells comprising the BBTB to increase barrier permeability. Cereport selectively increases permeability of the vasculature supplying brain tumors in rodent models of glioma (Bartus et al, 1996a, b; Elliott et al, 1996a, b;Matsukado et al, 1996) as well as in glioma patients Cloughesy et al, 1999;Ford et al, 1996).A potentially complicating factor with Cereport, or any pharmacologic approach intended to temporarily increase the permeability of the BBTB, is the possible interaction with other drugs commonly administered to glioma patients. For example, brain tumor patients typically receive corticosteroids, such as dexamethasone (Decadron ® ), to treat emesis and manage neurologic symptoms by decreasing intracranial pressure (reviewed in Glaser et al, 1997;Gutin, 1977;Koehler, 1995;Vecht and Verbiest, 1995).…”

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Cereport® (RMP-7) increases carboplatin levels in brain tumors after pretreatment with dexamethasone

Dean¹,

Emerich²,

Hasler³

et al. 1999

Neuro-Oncol

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Accumulating evidence suggests that dexamethasone might decrease permeability of the blood-brain tumor barrier, further limiting the delivery of agents into brain tumors. The bradykinin B 2 receptor agonist, Cereport ® (RMP-7), selectively increases permeability of the vasculature supplying brain tumors in both animal models and humans. The present study was conducted to characterize the effects of dexamethasone on the blood-brain tumor barrier and its potential interaction with Cereport's ability to enhance penetration of radiolabeled carboplatin. Dexamethasone (1.5 mg/kg/day, twice a day) was given to RG2 glioma-bearing rats via oral gavage for 3 consecutive days. After treatment, animals received a 15-min intracarotid infusion of Cereport (4.5 µg/kg) and a bolus of [ 14 C]carboplatin. The levels of [ 14 C]carboplatin (nCi/g) in the tumor and nontumor regions were determined at 1, 14, or 24 h after the last dose of dexamethasone. Dexamethasone, alone, significantly decreased the levels of radiolabeled carboplatin permeating the tumor (19%), although there were no signi cant differences between any of the time points examined. Cereport administration signi cantly increased levels of carboplatin in the tumor, independent of whether or not dexamethasone was given (46% with and 49% without). Although the relative effects of Cereport on tumor carboplatin levels were not affected by dexamethasone, the absolute levels achieved with Cereport were modestly reduced (44 nCi/g versus 55.5 nCi/g of [ 14 C]carboplatin, with and without dexamethasone, respectively). Thus, while the data support the use of Cereport as adjunctive therapy in the treatment of glioma patients, they also warn that the use of dexamethasone may reduce delivery of chemotherapeutic agents to brain tumors, even when special pharmacologic measures are employed to enhance delivery. Neuro-Oncology 1, 268-274, 1999 (Posted to Neuro-Oncology [serial online], Doc. 99-12, September 9, 1999 D espite substantial effort to develop new antineoplastic drugs, survival of malignant glioma patients has not been signi cantly improved (Nelson et al., 1993). One reason chemotherapeutic agents have not been more successful is the existence of the BBTB 2 (Groothius et al., 1982;Long, 1970;Neuwelt et al., 1982;Shibata, 1989). While the vasculature comprising the BBTB is known to be leaky compared with normal brain (Levin et al., 1975), it still offers signi cant resistance to water-soluble chemotherapeutic agents, thus impeding the entry of these drugs into the tumor.Over the past several years, a number of different techniques have been explored to increase permeability of the BBTB, with hyperosmotic disruption of the barrier being among the earliest (Neuwelt et al., , 1985Neuwelt and Rapoport, 1984). More recently, bradykinin (Black, 1995;Matsukado et al., 1998;Nomura et al., 1994) and the bradykinin agonist Cereport ® (RMP-7) (Bartus et al., 1996a, b;Doctrow et al., 1994;Straub et al., 1994) have been used to stimulate the receptors on the endothelial cells comprising...

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Enhanced Tumor Uptake of Carboplatin and Survival in Glioma-bearing Rats by Intracarotid Infusion of Bradykinin Analog, RMP-7

Cited by 149 publications

References 39 publications

Selective delivery of herpes virus vectors to experimental brain tumors using RMP-7

Selective delivery of herpes virus vectors to experimental brain tumors using RMP-7

Enhanced delivery of carboplatin into brain tumours with intravenous CereportTM (RMP-7): dramatic differences and insight gained from dosing parameters

Cereport® (RMP-7) increases carboplatin levels in brain tumors after pretreatment with dexamethasone

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