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PubMed1988

[UFT + MMC and UFT + ACNU therapy in advanced gastric cancer].

The effects of UFT + MMC and UFT + ACNU therapy on advanced gastric cancer were compared by randomized controlled trial in 12 institutions. Unresectable and postoperatively recurrent patients were divided into PS 0-2 and 3-4 groups. After classification according to cancer spread, such as localized type, hepatic metastatic type, ascitic type and distant metastatic type, regimens of (A) UFT 375 mg/m2/day + MMC 5 mg/m2 for 1-2 W or (B) UFT + ACNU 60 mg/m2/W/x2 (with a 4-week interval) were administered for as long as possible. As a result, among a total of 104 cases, responses were recognized in 7 out of 32 cases (21.9%) treated with regimen A and in 5 out of 25 cases (20.0%) treated with regimen B, giving a total of 57 evaluable cases excluding 33 incompletely evaluated cases and 14 ineligible cases. This study therefore demonstrated no significant difference between the two regimens. The median survival of patients treated with regimen A was 120 days, and that of patients treated with regimen B, 155 days. There was no significant difference between the two regimens. As side effects, UGI symptoms were recognized in 35.4% of regimen A patients and in 37.1% of regimen B patients. Bone marrow suppression appeared in 39.6% of regimen A patients and in 54.3% of regimen B patients.

Adenocarcinoma↗
PubMed1988

[A case report of brain metastasis due to an advanced gastric cancer].

In April 1984, a 49-year-old male underwent a partial gastrectomy for advanced gastric cancer. At that time, many metastatic foci were found, for example, in the rib, the lumbar vertebrae, the cervical vertebrae, and in the abdominal lymph nodes. Approximately one year later, he suddenly became disturbed and lost consciousness. A metastatic brain tumor was diagnosed. To destroy this tumor the patient received a course of irradiation therapy with a total dose of 45 gys directed toward head. Several months later, however, recurrence of the tumor was detected at the same intracranial region. Thus, a course of therapy, employing a combination of FT-207 and ACNU, was initiated against the recurrent tumor. Though the tumor was not eliminated, the patient manifested few of the prior symptoms. This state has continued for several months, with the patient having survived for three years after his gastrectomy. The following report will present the details of this case.

Brain Neoplasms↗
PubMedDate not supplied

Early stage detection of chemotherapeutic effect on 203 GL glioma in mice as studied by P-31 NMR and flow cytometry.

The effect of chemotherapy against glioma in mouse was evaluated by 31P NMR spectroscopy and flow cytometry. We found that administration of ACNU or tegafur at a dose less than LD50 resulted in the partial suppression of the ratio of inorganic phosphate (Pi)/phosphocreatine (PCr) and phosphomonoester (PME)/creatine phosphate (PCr) after 24 or 48 hr, although these ratios are usually increased together with growth of tumors. Flow cytometric analysis of glioma in vivo showed an accumulation in cells containing tetraploid DNA by G2M block 24-48 hr after treatment. However, the change occurred at a period slightly later than that of the Pi/PCr ratio. In contrast, histological change was noted at eight days after administration. Hence, it is concluded that in vivo 31P NMR spectroscopy can detect a change in metabolic pathways in tumors as early as 24-48 hr after the administration of chemotherapeutic agents.

Animals↗
PubMed1985

[New developments in chemotherapy for experimental brain metastasis].

Numerous animal models of brain tumor have been developed for screening new chemotherapeutic agents effective for brain tumors. However, most of these models have problem (s) of mechanical disruption of the blood-brain barrier by tumor inoculation and/or discrepancy in histologic nature and site of growth between inoculated tumors and human tumors. With the purpose of establishing a better model for the evaluation of antitumor activity, we have developed rat models of leptomeningeal tumors by intralateral-ventricle inoculation of myelogenous leukemia cells (DBLA-6) or AH130 ascites hepatoma cells. It was proved that in the two models there was no disruption of blood-brain barrier function by tumor inoculation and that the histologic pattern of DBLA-6 model tumor closely resembled the diffuse meningeal involvement of leukemic cells seen in the human disease. Using these models, several antitumor agents have been tested and ACNU, CCNU and procarbazine were found to be highly effective when given intravenously or intraperitoneally, and the intralateral-ventricle administration of methotrexate was also found to show a moderate antitumor activity. Furthermore it was found that intraperitoneal administration of spirohydantoin mustard, and intralateral-ventricle administration of 5-fluorodeoxyuridine were highly effective against the AH130 model.

Animals↗
PubMed1985

[Clinico-immunological evaluation of T cells bearing IgG Fc receptors in brain tumor patients].

T cells bearing IgG Fc receptors (Tr cells) were determined in 40 cases of brain tumor using the double rosette method, and compared with the changes of PHA reaction, immunoglobulin (IgG A M), performance status, and mass effect on CT in 20 pre-and post-operative and/or radio-clinico-immunotherapeutic patients. The proportion of control Tr cells was 8-19% in 20 healthy adults. Values of Tr cells over 20% were correlated with a poor grade of performance status, and large mass effects on CT. Post-therapeutic change in the value was well correlated with change in performance status, mass effects, and IgG. Our results suggest a correlation between the value of Tr cells and clinico-radiological findings. Immunological analysis of Tr cells serves as a parameter of tumor expansion or prognosis, and could be of significant importance clinically.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Hyperbaric oxygenation for experimental bladder tumor. II. Hyperbaric oxygenation in combination with chemotherapy in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder tumors.

Two series of experiments were conducted to ascertain whether hyperbaric oxygenation (HBO) treatment with or without antineoplastic chemotherapy can really suppress tumor development in N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder tumor in rats. HBO treatment of 2 ATA of air saturating with 30-35% of oxygen for 90 min daily plus 0.5 mg/100 g body weight of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) administration for 5 times suppressed the neoplastic spread of the bladder for 9 weeks and reduced the bladder weight in BBN-treated rats. Similar effects were also obtained in ACNU-treated rats, but to a lesser extent. HBO treatment associated with or without doxorubicin failed to suppress tumor growth in BBN-treated animals. Based on these findings combined with the previous study (part I), HBO treatment associated with ACNU might be available for the treatment of some cases of bladder tumors.

Animals↗
PubMed1988

[Response to antitumor agents of human transplantable glioma implanted into chorioallantoic membrane of chick embryo].

In case of chemotherapy against brain tumors, it is most important to choose suitable drugs for brain tumors, since human tumors have different drug sensitivity and growth. Heretofore, the nitrosourea-induced rat glioma cell, such as C6, or immunodeficient mice were usually used for predicting the drug sensitivity of brain tumors. We took notice of Murphy's system for the chemosensitivity test, in which a human tumor is transplanted into the chorioallantoic membrane (CAM) of a chick embryo. By modifying the conventional Murphy's system, we studied the efficiency of this system in predicting the drug sensitivity of brain tumors. First, we compared the result of a drug sensitivity test using CAM of a chick embryo with that using nude mice. Next we studied the effect of chemotherapeutic agents against brain metastasis of a chick embryo caused by the intravenous injection of mouse B16 melanoma cells. The tumor reduction rate of the sensitivity test using a chick embryo tended to agree with that using nude mice. In the drug sensitivity test against brain metastasis, ACNU was the most effective. This result supports the result of the clinical study. In conclusion, the drug sensitivity test using a chick embryo is thought to be useful and the advantages or disadvantages of this system are discussed.

Allantois↗
PubMed1988

[Mechanisms of cellular resistance to chloroethylnitrosourea in cell lines derived from human brain tumors].

The cytotoxic and cytogenetic effects 1-(4-amino-2-methyl 1-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU) treatments on five cell lines derived from human malignant glioma were studied. Compared to sensitive cell line SF-126, SF-188 cells were 3- to 6.9 fold more resistant to the cytotoxic effect and 8 to 14 fold more resistant to the induction of sister chromatid exchanges (SCEs). Cytotoxic effects and induction of SCEs were intermediate for SF-268, SF-210 and SF-295 cell lines compared with SF-126 and SF-188. There was a good correlation between susceptibility to the cytotoxic effects and formation of DNA interstrand crosslinks for cells treated with ACNU and BCNU. The effects of cis-diamminedichloroplatinum (II) (cis-Pt) and nitrogen mustard (HN2) in these cells were also studied. Cis-Pt was equally cytotoxic and induced the same number of SCEs and DNA interstrand cross-links in all five cel lines. In contrast to the results obtained by treatment with chloroethylnitrosoureas (CENUs), SF-126 cells treated with HN2 were more resistant to the cytotoxic effects, the induction of SCEs, and the induction of DNA interstrand cross-links than were SF-188 cells. The repair of O6-methylguanine after treatment of these cell lines with (3H) methylnitrosourea were quantitated. SF-126 cells showed no detectable repair of O6-methylguanine, SF-268, SF-210 and SF-295 cells had intermediate levels of repair, and SF-188 had very high level of repair. These results suggest that cellular resistance to CENUs dose not result in cross-resistance to HN2 or cis-Pt, and that one of mechanisms of cellular resistance to CENUs is increased repair of O6-alkylguanine derivatives in DNA, which prevents DNA interstrand cross-links and then reduces both cytotoxic effects and the induction of SCEs in cell resistant to CENUs.

Brain Neoplasms↗
PubMed1988

[Biological basis for combined radio-chemotherapy in radioresistant tumors].

Human tumor cells such as melanoma or glioblastoma are intrinsically radioresistant on an average than cells of more common tumors in radiotherapy such as squamous cell carcinoma or adenocarcinoma. Mean inactivation dose (D) for glioblastoma A-7 cells was 3.1 Gy for cells growing exponentially, but was 4.3 Gy for cells grown in large spheroids with hypoxic cells and PLD recovery. The D for cells of squamous cell carcinoma was about 2.1 Gy. This indicates that local control of the radioresistant tumors may be achieved if a drug showing an enhancement ratio of about 2.0. Data on our experiments with others in the literature indicate that drugs which selectively sensitize hypoxic cells and inhibit PLD recovery may be useful to increase the therapeutic ratio. Experimental evidence on a nitrosourea, ACNU has been presented for such mechanisms of the action. Multivariate analysis with Cox's model on malignant gliomas of 209 patients indicated that a significant increase in the survival time was obtained in the radiotherapy combined with ACNU.

Antineoplastic Agents↗
PubMed1988

[Effect of ACNU against experimental brain tumor--immunohistochemical study using anti-BrdU monoclonal antibody].

We have studied the efficacy of intrathecal ACNU against experimental leptomeningeal tumors. In the present report, the effect of ACNU on the growth kinetics of the tumor was evaluated by the immunohistochemical technique using anti-BrdU monoclonal antibody. The experimental leptomeningeal tumor was developed by inoculation of Walker 256 carcinosarcoma cells into the cisterna magna of rats. Seven days after the inoculation of tumor cells, the animals were treated either by intravenous (15 mg/kg) or intrathecal (1.5 mg/kg) ACNU. Four, 12, 24, 48, 96 or 144 hours after treatment, the animals received intravenous BrdU (200 mg/kg). Thirty minutes thereafter, they were sacrificed and the brain was removed. L. I. was calculated by counting the immunoreactive tumor cells. L. I. of the tumor without treatment on the seventh day after inoculation was over 40%. L. I. began to decrease 24 hours after intravenous ACNU, and remained 11% up to 96 hours. On the other hand, L. I. already decreased to 20% 4 hours after intrathecal ACNU and remained to be low (17%) up to 48 hours. However, L. I. increased to 38% at 96 hours. Thus, the effect on the growth kinetics of the tumor differs between intravenous and intrathecal ACNU. These results are considered to be useful informations for determining the optimal dosage of the antineoplastic agent against the brain tumor and developing the effective combination chemotherapy.

Animals↗
PubMed1987

[An autopsy case of neurocutaneous melanosis associated with intracerebral malignant melanoma].

The authors reported the clinical course and the postmortem examination of a unique case of neurocutaneous melanosis with numerous anomalies and complications, which included congenital dislocation of lenses, hypogonadism, ectopia of prostatic duct, genuine phimose, retentio testis, psina bifida and neurogenic bladder. This 13-year-old boy with a large hairy nevus in a bathing trunk configulation and multiple small nevi over the whole body since his birth was admitted to our hospital for evaluation of headache and vomiting. Neurological examination showed bilateral papilledema and slight left hemiparesis. A CT scan revealed a large right frontal mass and craniotomy was performed with subtotal removal of this tumor which was confirmed as a malignant leptomeningeal melanoma. He initially made uneventful postoperative recovery, and two courses of chemotherapy with DTIC, ACNU and VCR were given; however, the currence of brain tumor ensued shortly thereafter, and he died in approximately six months after the onset of intracranial symptoms despite of the third course of chemotherapy. Thirty five cases of neurocutaneous melanosis associated with or without malignant melanoma have been reported in Japan. Twenty-eight cases were male and 7 female. Two cases showed the evidence of primary malignant melanoma outside of the central nervous system, whereas twenty eight leptomeningeal melanoma, in which 22 were solid and 6 diffuse, were shown intracranially. Other 5 cases had epileptic seizure and/or hydrocephalus caused by wide spreaded leptmeningeal melanosis. This high incidence of intracranial malignant melanoma in this disorder was remarkable compaired with the previous reports in other countries. Mean duration between deaths and the onset of symptoms of intracranial hypertension or focal neurological signs was 7 months, ranging from 1 to 24 months, showing the rapidly deteriorating course in this disorder.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

[Analysis of DNA damage induced by nitrosourea derivatives in rat brain tumor cells using a sequencing procedure].

DNA damages caused by various anticancer nitrosourea compounds such as ACNU and MCNU were studied. Reiterated fragments of 167 and 203 base pairs (bp) were obtained after Hind III and Hae III restriction endonuclease digestion of 9L rat brain tumor DNA. The end-labeled reiterated fragments were reacted with ACNU and MCNU, which resulted in the scission breaks corresponding to the locations of guanine on an extended Maxam-Gilbert sequencing gel. Subsequent piperidine hydrolysis yielded scission products more frequently. These results indicate that nitrosoureas such as ACNU and MCNU generate DNA scission breaks and/or alkali-labile sites preferentially at the position of guanine moieties in rat brain tumor DNA.

Animals↗
PubMed1986

[Combination therapy with IFN-beta, ACNU and radiation (IAR) in malignant brain tumors].

In order to analyze the efficacy of combination therapy with Hu-IFN-beta, ACNU and radiation (IAR), nine patients with malignant glioma were treated as a control study. They received 100 X 10(4) IU Hu-IFN-beta daily for seven days intravenously or intratumorally, 3 mg/kg ACNU on day 2 and 5,000-6,000 rads of radiation from day 3. Four out of nine patients showed complete response and one partial response with this IAR therapy. Case 1 was a 64-year-old man who had glioblastoma in the left frontal lobe. Postoperative residual tumors disappeared completely with this therapy. Case 3 was a 8-year-old girl who had an enhanced high-density lesion in the medulla oblongata and pons. After IAR therapy, the high-density lesion was completely vanished and her clinical manifestations of multiple cranial nerve palsy and pyramidal sign were improved remarkably. The major side effects of IAR therapy were mild or moderate myelosuppression, and some patients also showed hepatic dysfunction, mild fever and gastrointestinal toxicities. However, all these side effects were mild and transient and soon recovered to normal levels. These results suggest that IAR therapy is effective and will prolong the survival time of patients with malignant glioma.

Adolescent↗