Kouichi Tokuda

Modification of tumor blood flow and enhancement of therapeutic effect of ACNU on experimental rat gliomas with angiotensin II

Blood flow was measured in transplanted rat gliomas before and during a constant intravenous infusion of angiotensin II using hydrogen clearance methods. The brain tumor models were produced in syngeneic Wister-King-Aptekman male rats with stereotaxic inoculation of ethylnitrosourea-induced glioma cells (KEG-1). Induced hypertension up to 150 mmHg (mean arterial pressure) with the infusion of angiotensin II resulted in a significant increase of blood flow to tumor center compared to the normotensive state (p < 0.001). Blood flow measured simultaneously in brain tissue of tumor-free contralateral hemisphere did not change.The therapeutic effect of administration of the simultaneous 1-(4-Amino-2-methyl-5-pyrimidinyl)methyl3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and angiotensin II was evaluated in four experimental groups with the tumor-bearing rats. Twelve days after tumor implantation, the rats were administered angiotensin II to increase the mean arterial blood pressure to 150 mmHg, followed by intravenous injection of ACNU injection. The increased blood pressure was steadily maintained for 20 minutes. The ACNU/induced hypertension group showed a median survival time of 27.0 days, which was significant longer (p < 0.02) than that of an ACNU treatment group (22.0 days), a hypertension treatment group (19.0 days), or a no treatment group (18.5 days).The enhanced therapeutic effect can be attributed to improving chemotherapeutic drug delivery due to increased blood flow in the tumor.

Diagnostic impact of baseline cerebral blood flow in patients with acute ischemic stroke prior to intravenous recombinant tissue plasminogen activator therapy

OBJECTIVE To determine whether severe cerebral perfusion defects measured by SPECT prior to rt-PA therapy attribute to severe intracerebral hemorrhage (SICH). METHODS We measured baseline cerebral blood flow (CBF) using technetium-99m-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT qualitatively prior to rt-PA therapy, in 52 consecutive patients (range 38-93 years). The degree and extent of the asymmetry of local CBF were analyzed semi-quantitatively. We did not administrate rt-PA in patients with severe perfusion defects. Clinical outcome and the incidence of SICH were studied. RESULTS Three (5.8%) patients had severe perfusion defects that were undetected by CT and/or DWI. The other 49 (94.2%) patients had mild perfusion defects. The asymmetry of local CBF was 0.08±0.08 (n=3) and 0.3±0.15 (n=49) in the two groups, respectively. The percentages of the ipsilateral hemisphere in which perfusion was impaired severely were 17.5±9.5% (n=3) and 0.43±0.87% (n=49). Two patients were found petechial hemorrhage, but there was no patient who developed SICH in the former group following conventional antithrombotic therapy. In the latter group, SICH occurred in 1/49 (2.0%) patient following rt-PA therapy. CONCLUSION These results suggest that rt-PA therapy for patients with severe cerebral perfusion defects may cause SICH and baseline CBF may contribute to identify patients at high risk for SICH after intravenous rt-PA therapy.

Potentiation of 3-(4-Amino-2-Methyl-5-Pyrimidinyl) Methyl-1-(2-Chloroethyl)-Nitrosourea Cytotoxicity in Resistant Human Glioma Cell by Pretreatment with 5-(3-Methyl-1-Triazeno) Imidazole-4-Carboxamide

In our previous studies, we reported the results that O6-alkylguanine DNA alkyltransferase (O6-AT) plays an important role in determining the cellular resistance to treatment with chloroethylnitrosourea (CENU) [1–3]. The mechanism of cellular resistance has not been fully understood, but it is clear that O6-AT repairs O6-chloroethylguanine before it can rearrange to form the DNA interstrand cross-link [4–5], and this results in cellular resistance to the cytotoxic effects of CENUs. O6-AT also prevents the induction of sister chromatid exchanges (SCEs) by CENUs, since the increased induction of SCEs is due to higher levels of DNA interstrand cross-links [1,2,6]. The reduction of O6-AT activity in tumor cells which are resistant to CENUs may be used to improve the clinical effectiveness of CENUs, since this activity protects the cytotoxic effects of these agents. This has been approached by pretreatment with a monofunctional methylating agent [2,7,8]. 5-(3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) is a chemotherapeutic agent used primarily to treat malignant melanoma, sarcoma, and lymphoma. DTIC requires metabolic activation through oxidative N-demethylation leading to the formation of the N-demethyl derivative, 5-(3-methyl-1-triazeno) imidazole-4-carboxamide (MTIC), a potent alkylating agent. Recently, MTIC has been shown to alkylate DNA in the O6 of guanine and to be more cytotoxic in O6-AT deficient cells (Mer−) than in O6-AT proficient cells (Mer+) [9,10].

Loss of Heterozygosity of Chromosomes 10 and 17 in Human Malignant Astrocytomas

Astrocytomas are the most common tumors of the human central nervous system. Tumors of this type can be classified into four histopathologic grades of malignancy according to Kernohan [1]. Glioblastoma (astrocytoma grade IV) is always lethal despite surgery, radiotherapy, and/or chemotherapy. Low-grade or anaplastic astrocytomas vary in their response to treatment. However, a recurrent tumor is often less well differentiated, suggesting that astrocytoma can be a progressive disease. It is now believed that the genes responsible for tumorigenesis are recessive oncogenes.