Paralytic ileus associated with a combination of dacarbazine-nimustine hydrochloride-vincristine chemotherapy.
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[Clinical or experimental use of an anticancer drug-oil suspension and its characteristics].
The anticancer agent, Nimustine, which is a derivative of Nimustine hydrochloride (Sankyo CC, Ltd), was suspended in an oil, Lipiodol, using an ultrasonic suspender and used in experimental animals and human subjects with malignant tumor. The use of Lipiodol facilitates the fluoroscopic demonstration of the site into which the suspension has been injected. The Nimustine-Lipiodol suspension was almost stable in room air over 7 days and diffusion of suspended Nimustine into saline in vitro was still noted 4 weeks later. Remarkable regression of tumor size was observed when the Nimustine-Lipiodol suspension was locally injected into the lesion of Lewis lung cancer subcutaneously inoculated into mice. Moreover, a marked regression of tumor size and improvement of CEA level in serum were also obtained when arterial injection of the Nimustine-Lipiodol suspension was carried out in patients with metastatic liver cancer. Therefore, local or arterial injection of Nimustine-Lipiodol suspension is considered to be effective as a method of cancer targeting therapy.
Animals↗
Evaluation of antitumor activity in a human breast tumor/nude mouse model with a special emphasis on treatment dose.
Eight lines of human breast tumors implanted in nude mice were treated with various antitumor agents at two different doses, maximum tolerated doses (MTD) and rational doses (RD) that were pharmacokinetically equivalent to the clinical doses; the response rates to both doses were compared. With MTD, the response rates to mitomycin C and vinblastine were 100%, and those to other agents including cyclophosphamide, nimustine (a water-soluble nitrosourea), vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 5-fluorouracil (5-FU), and methotrexate were 30%-50%, indicating high responsiveness to the former two agents. In contrast, when the RD were used, the response rates to the majority of these agents were 25%-40%, and those to vincristine and nimustine were 13% and 0%, respectively. These results agree with the reported clinical results compared with those with MTD, suggesting the importance of the use of clinically equivalent doses in the evaluation of antitumor efficacy in a human tumor/nude mouse system.
Animals↗
Activity of cytostatic drugs in two heterotransplanted human testicular cancer cell lines with different sensitivity to standard agents.
Two established human testicular cancer cell lines were used in a mouse xenograft model to assess the antitumour activity of 15 anticancer agents. Line H 12.1 was highly sensitive to cisplatin, bleomycin and vinblastine, resembling non-pretreated testicular tumours, whereas line H 23.1 showed resistance to cisplatin and vinblastine, comparable to tumours with acquired or intrinsic drug resistance. In line H 12.1 several drugs were highly active, including cyclophosphamide, ifosfamide, nimustine and vincristine; carmustine, vindesine, doxorubicin, epidoxorubicin, pirarubicin, mitoxantrone, carboplatin and iproplatin had only moderate activity. In line H 23.1 only cyclophosphamide, ifosfamide, nimustine, vincristine and bleomycin had antitumour activity. These two cell lines represent a useful model for preclinical evaluation of new agents with presumed activity in testis cancer.
Animals↗
Chemosensitivity test for human small cell lung cancer cell lines in vitro.
The in vitro response to seven chemotherapeutic drugs of three established human small cell lung cancer (SCLC) cell lines (NCI H69, H128, N231) was tested by a double soft agar clonogenic assay. Colony formation by the three cell lines was universally reduced more than 50% by continuous exposure to peak plasma concentrations of all the drugs. However by exposure to one-tenth of the peak plasma concentrations, the colony growth of H69 was reduced to 25.6% and 37.7% by etoposide and teniposide, respectively, and that of N231 was reduced to 46.7%, 39.0%, 27.5% by carboplatin, etoposide and teniposide, respectively. On the other hand colony formation by the three cell lines was not suppressed more than 50% by one-hour exposure to any of the drugs tested at one-tenth of the peak plasma concentrations. By one-hour exposure to drugs at the peak plasma concentrations, colony formation by H69, H128 and N231 was reduced more than 50% by cisplatin, etoposide, teniposide and nimustin, by adriamycin, teniposide and ACNU, and by adriamycin, etoposide, teniposide and nimustin, respectively. It was concluded that these three cell lines have similar sensitivity to seven drugs commonly used against small cell lung cancer.
Antineoplastic Agents↗
Sensitivity of anticancer drugs in NIH3T3' cells transfected with oncogenes accompanied by pSV2neo vector.
NIH3T3 cells and NIH3T3 cell lines, which were transfected with several oncogenes accompanied by pSV2neo vector, were observed for their survival rate when treated with commonly used anticancer drugs. The survival rates in the cell line transfected with the pSV2neo vector only did not differ significantly from that of parental NIH3T3 cells against bleomycin, nimustine and adriamycin, but it was significantly more resistant to cisplatin and more sensitive to mitomycin C. Therefore, the survival rate in each transfectant was compared with that in the pSV2neo transfectant. The Val-12, v-Ha-ras, v-int-2, v-erbB or v-abl transfectants accompanied by pSV2neo vector were significantly more sensitive to cisplatin than transfection with pSV2neo vector only. The Val-12, v-Ha-ras, v-int-2 and v-abl transfectants were significantly more sensitive, and the v-erbB transfectant more resistant to bleomycin than the pSV2neo transfectant. The v-int-2, v-erbB, frg, v-raf and v-myc transfectants were more sensitive, and the v-Ha-ras transfectant more resistant to nimustine than the pSV2neo transfectant. The N-ras, v-Ha-ras, v-sis, v-int, v-abl and v-myc transfectants were significantly more sensitive to adriamycin than the pSV2neo transfectant. The v-sis and v-int-2 transfectants were more sensitive, and the c-Ki-ras, Val-12, v-erbB and the v-src transfectants more resistant to mitomycin C than the pSV2neo transfectant. Thus there was no relationship between the drug sensitivity and the location of oncogenes, but the transfection was associated with either increased or decreased sensitivity to a number of commonly used anticancer drugs. Therefore, it may be important to take into consideration or overexpression of oncogenes in cancer chemotherapy.
3T3 Cells↗
p53-independent WAF1 induction by ACNU in human glioblastoma cells.
The induction of WAF1 gene expression after the treatment with the anticancer agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU; nimustine hydrochloride) was studied in two human glioblastoma cell lines: U-87MG, which bears the wild-type p53 gene, and T98G, which bears the mutant p53 gene. A marked accumulation of WAF1 was observed 3 h after ACNU treatment in both cell lines. The induction of WAF1 mRNA by ACNU was detected by northern blot analysis in these cells. Binding activity of p53 to a p53 consensus sequence increased after treatment in U-87MG cells but not in T98G cells. The existence of a p53-independent WAF1 induction pathway was supported by the apparent accumulation of WAF1 after ACNU treatment in the p53-null human osteosarcoma cell line Saos-2. These findings suggest that there are two possible pathways for WAF1 induction: the p53-dependent pathway through the p53-responsive element and the p53-independent pathway through other elements.
Antineoplastic Agents↗
A randomized prospective study of radiation versus radiation plus ACNU in inoperable non-small cell carcinoma of the lung. Japan Radiation-ACNU Study Group.
Between February 1983 and January 1986, 77 evaluable patients with non-small cell lung cancer were randomized to receive radiotherapy with or without nimustine hydrochloride (ACNU) according to a centralized resistration system using a telephone call. The randomization was for radiation 50 to 60 Gy/5 to 6 weeks with or without ACNU (30 mg/m2 x 4 times) during irradiation. There were no significant differences in the patient characteristics of either group. The complete response rates to both regimens were statistically significantly different: 55% in radiation plus ACNU and 13.6% in radiation alone for squamous cell carcinoma. In addition, there were statistically significant differences in Stage III. The median survival time for radiation plus ACNU was 47.7 weeks, compared with 41.9 weeks for radiation alone. Overall survival did not significantly differ in either group. There was a significant decrease in the incidence of leukocyte nadirs below 2000/ml (5.7%) and platelet 50,000/ml (14.3%) with ACNU. This study confirmed that radiation with ACNU in the treatment of non-small cell lung cancer was effective and superior as compared to radiation alone.
Adenocarcinoma↗
In vitro measurement of chemosensitivity of human small cell lung and gastric cancer cell lines toward cell cycle phase-nonspecific agents under the clinically equivalent area under the curve.
BACKGROUND: Based on the previous finding that cell killing effects of cell cycle phase-nonspecific agents depend on the concentration-time product (C x T) or the area under the curve (AUC), the authors investigated in vitro cytotoxic effects of nimustine hydrochloride (ACNU) and mitomycin C (MMC) under an experimental condition in which the assay AUC was equivalent to their clinically achievable AUC. METHODS: The cytotoxic effects of these agents on human cancer cell lines, consisting of 9 small cell lung carcinomas (SCLC) and 10 gastric cancers, were measured by a tetrazolium-based colorimetric assay (MTT assay). RESULTS: These cell lines individually responded to ACNU and MMC in this assay condition. When the authors considered 60% or greater cell kill to be effective, the in vitro response rates of SCLC to ACNU and MMC were 22% (two of nine carcinomas) and 67% (six of nine carcinomas), respectively. The response rates of gastric cancer to ACNU and MMC were 10% (1 of 10 carcinomas) and 40% (4 of 10 carcinomas), respectively. Except for the response of SCLC to ACNU, these in vitro response rates corresponded well to the clinical rates (SCLC to ACNU and MMC, 47% [14 of 30 carcinomas] and 50% [17 of 34 carcinomas], respectively; gastric cancer to ACNU and MMC, 11% [4 of 37 carcinomas] and 30% [63 of 211 carcinomas], respectively). CONCLUSIONS: These results suggest that the introduction of the clinically equivalent AUC to the in vitro chemosensitivity test for cell cycle phase-nonspecific agents may improve its clinical predictability.
Carcinoma, Small Cell↗
A strategy for selective anti-cancer drug concentration increase in rat glioma tissue with Ca(2+)-channel blocker co-administration: calcium kinetics in intra-glioma arteriolar smooth muscle cells.
A rat glioma model was employed to estimate the Ca2+ kinetics in the tumor arteriolar smooth muscle cells. Electron microcytochemistry revealed that the density of intracellular Ca2+ deposits in the intra-tumor arteriolar smooth muscle cells was significantly greater, with slightly higher membrane Ca(2+)-adenosine triphosphatase (ATPase) activity, compared to the contralateral cerebral arterioles. Furthermore, the administration of tyrphostin, a tyrosine kinase inhibitor, specifically increased only the intra-tumor blood flow. These findings suggest that the condition of the intra-tumor arteriole alters the susceptibility to contraction by the accelerated Ca2+ influx into the cytoplasm mediated through the tyrosine kinase pathway. After the administration of diltiazem, which also has a blocking effect on the Ca(2+)-channel mediated through this pathway, the local intra-tumor blood flow showed an increase of 39% with a marked decrease of intracellular Ca2+ concentration of the arteriolar smooth muscle cells in the tumor, while the blood flow in the basal ganglia increased by only 8%. The intra-tumor concentration of Nimustine-HCl (ACNU) with co-administration of diltiazem was significantly increased compared to that without the co-administration. Co-administration of diltiazem may be a valuable strategy in chemotherapy for glioma in affording the selective increase of intra-tumor concentration of the anti-cancer drug.
Animals↗
Thermal enhancement of ACNU and potentiation of thermochemotherapy with ACNU by hypertonic glucose in the BT4An rat glioma.
Hyperthermia increases the cytotoxicity of the nitrosourea BCNU (carmustine). Glucose given before treatment may further increase the value of thermochemotherapy, presumably by lowering tumour pH through blood flow reduction. The water-soluble ACNU (nimustine) is an alternative to other nitrosoureas in the treatment of gliomas. The drug is soluble without use of ethanol, and the eye complications when given intra-arterially are reduced compared with similar use of BCNU. The influence of simultaneous hyperthermia on treatment with ACNU, and the value of glucose administered before thermochemotherapy therefore were investigated in the malignant rat glioma BT4An. BD IX rats with subcutaneous BT4An tumours on the hind leg were treated with ACNU (i.p.), or ACNU and locally applied waterbath hyperthermia (44 degrees C for 45 min), with or without previous glucose (6 g/kg i.p. 2 hours before treatment). ACNU (10 or 20 mg/kg) alone and ACNU (20 mg/kg) after previous glucose did not influence tumour growth, compared to the controls. Simultaneous ACNU (10 mg/kg) and hyperthermia clearly was more effective than treatment with hyperthermia alone. Glucose load before treatment further enhanced the effect of combined ACNU and hyperthermia. Glucose before treatment did not change local toxicity or weight profiles of treatment with ACNU alone, or simultaneous ACNU and hyperthermia. Glucose load therefore represented a therapeutic gain when administered before thermochemotherapy with ACNU.
Animals↗
Uptake of drugs and expression of P-glycoprotein in the rat 9L glioma.
Two weeks after the inoculation of 1.5 x 10(5) 9L glioma cells into the rat brain, the uptake of radiolabelled drugs into the brain and the experimental 9L glioma during the first cerebral circulation was measured with a liquid scintillation counter and analyzed by the method of Oldendorf (1970). The expression of P-glycoprotein, which is known to be associated with the efflux of drugs, was also studied, using anti-P-glycoprotein monoclonal antibody, C-219. Furthermore, the ultrastructure of brain capillaries, tumor vessels, and glioma cells was studied by conventional and immunoelectron microscopy. Sucrose (control), the transport of which through the blood-brain barrier is known to be negligible, accumulated to fivefold higher levels in the tumor than in normal brain. Ranimustine (MCNU), 5-fluorouracil (5-FU), and doxorubicin showed little accumulation in the normal brain, whereas nimustine (ACNU) showed an increased accumulation. MCNU and doxorubicin showed negligible accumulation in the glioma cells despite diffusion into the tumor interstitial space. In contrast, ACNU and 5-FU showed an increased accumulation in tumor cells. The accumulation of 5-FU in the cultured 9L glioma cells was decreased by ATP inhibitors or by low temperature. Although both brain capillary endothelial cells and glioma cell membrane were immunohistochemically positive for P-glycoprotein, the tumor vasculature showed low expression of P-glycoprotein. The endothelial cells of tumor vessels ultrastructurally showed increased fenestrations, swelling, and disrupted junctions. Accordingly, it is suggested that hydrophobic drugs such as doxorubicin, being pumped out by P-glycoprotein, do not accumulate in 9L glioma cells as do other lipophilic drugs such as ACNU, or drugs such as 5-FU, which accumulate by a carrier-mediated mechanism.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A standardized method of using nude mice for the in vivo screening of antitumor drugs for human tumors.
Human tumors transplanted into nude mice have long been used to assess the effectiveness of antitumor drugs and yet there is still no established standard method in preclinical practice for screening new antitumor drugs in vivo using nude mice. Thus, a cooperative study on the feasibility of a human tumor/nude mouse system for the in vivo screening of drugs was conducted by the Japanese Research Society for Chemosensitivity of Cancer. Two human stomach cancers, H-111 and SC-6-JCK, and one human colon cancer, Co-4, were transplanted serially into nude mice and used as gastrointestinal tract tumors with stable tumor growth. The appropriate dosage of six well-known antitumor drugs [mitomycin C (MMC), cyclophosphamide (CPA), nimustine hydrochloride 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), cis-platinum (II) diaminodichloride (CDDP), adriamycin (ADM) and 5-fluorouracil (5-FU)] in human tumor-bearing nude mice was determined based on the maximum tolerance dose of the drug. The respective dosages were 6 mg/kg of MMC x 1 (i.p.), 120 mg/kg of CPA x 1 (i.p.), 30 mg/kg of ACNU x 1 (i.p.), 8 mg/kg of CDDP x 1 (i.p.), 8 mg/kg of ADM x 1 (i.v.), and 50 mg/kg of 5-FU q4d x 3 (i.p.). Three weeks after treatment, drug effectiveness was judged by the tumor growth inhibition rate. Treatment with these appropriate doses appeared to show the maximum effect of the respective drugs on the tumor-bearing nude mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Prediction of ACNU plasma concentration-time profiles in humans by animal scale-up.
Plasma concentration-time profiles of nimustine hydrochloride, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosour ea hydrochloride (ACNU), in the mouse, rat, rabbit, and dog were determined by high-performance liquid chromatographic analysis. The pharmacokinetic parameters for these four animal species and previously reported clinical data were analyzed for investigation of interspecies correlation. Log-log plots of body weight (W; kg) vs total plasma clearance (CLtot,p; ml/min) and steady-state distribution volume (Vd,ss; l) for the four animal species were linear, with high correlation coefficients (r 0.996 for both parameters), despite the fact that the nonrenal clearance was greater than 97% in these species. Linear regression on the plots excluding human data yielded allometric equations (CLtot,p = 50.6 W0.957; Vd, ss = 1.29 W1.03) that were extrapolated to predict ACNU pharmacokinetic parameters in humans. For both parameters, however, there were 3-fold differences between the predicted and observed parametric values. To investigate these discrepancies, we measured serum protein binding of ACNU in these animal species and in humans. The values of CLtot,p and Vd,ss were converted into those of CLutot,p and Vd,uss, which correspond to the parameters for unbound ACNU. In this case, correlation coefficients of the log-log plots excluding human data (CLutot,p = 71.7 W0.891; Vd,uss = 1.82 W0.966) were also high (r greater than or equal to 0.991). The extrapolated values vs those observed in a 70-kg human were the following: CLutot,p, 3,160 vs 2,290 ml/min; Vd,uss, 110 vs 106 l. Thus, the animal data were successfully extrapolated to yield better predictions of human pharmacokinetic parameters if the analysis was based on the unbound plasma concentration of ACNU. In addition, the predicted plasma concentration-time profile for humans also showed good agreement with the observed ones. These results suggest the importance of measuring unbound fractions of drugs for more accurate prediction of human pharmacokinetic parameters by extrapolation of animal data to the human situation.
Animals↗
Early and late stage positron emission tomography (PET) studies on the haemocirculation and metabolism of seemingly normal brain tissue in patients with gliomas following radiochemotherapy.
Haemocirculatory and metabolic changes in seemingly normal brain tissue following radiochemotherapy including nimustine hydrochloride (ACNU) and tegafur (FT) were analyzed using oxygen-15 and fluorine-18 positron emission tomography (PET) in seven patients with gliomas. At an early stage (within one month) after radiochemotherapy, marginal increases in regional cerebral blood flow (rCBF) and cerebral blood volume (rCBV) were found contralateral to the tumour in gray matter which was apparently normal brain structure, as seen on computerized tomography (CT). The oxygen extraction fraction (rOEF) decreased significantly (p less than 0.05 by a paired-t test) from that of the pretreatment study, due to surgical decompression and radiochemotherapy. At the late stage (three to thirty-one months with a mean of thirteen months), rCBF decreased significantly from the early stage study (p less than 0.05); oxygen consumption (rCMRO2) fell in all cases significantly from the pretreatment study (p less than 0.01) and from the early stage study (p less than 0.05); consequently, rOEF remained unchanged at a level similar to the early stage study. Glucose consumption (rCMRG1) increased slightly as compared with the early stage study but failed to be restored to the level of the pretreatment study. Noteworthy was a coupling reduction of rCBF and rCMRO2--presumably, a late delayed effect of radiochemotherapy. These preliminary results indicate that with PET studies it may be possible to predict damage to normal brain tissue after radiochemotherapy.
Adolescent↗
Linkage between O6-methylguanine-DNA methyltransferase (O6-MT) activity and cellular resistance to antitumour nitrosoureas in cultured rat brain tumour cell strains.
We have examined O6-methylguanine-DNA methyltransferase (O6-MT) activity of rat brain tumour cell strains with reference to cellular resistance to antitumour nitrosoureas, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (nimustine, ACNU) and methyl-6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyrano side (ramustine, MCNU). The values of O6-MT activity were 52 and 160 fmol/mg protein extract in 9L and C6 rat brain tumour cells, respectively; while HeLa S3 cells, as a methyl excision repair positive (Mer+) cell strain, revealed a rather high value of 488 fmol/mg. 9L cells indicative of a low O6-MT activity showed 13 microM for ACNU and 18 microM for MCNU at a 10% survival dose (SD10), determined by a clonogenic cell assay as an index of cellular resistance. In contrast to this, C6 cells revealed a SD10 value of 67 microM and 36 microM for ACNU and MCNU, respectively, indicating higher resistance than 9L cells. HeLa S3 cells showed the highest SD10 value as follows: 84 microM for ACNU and 73 microM for MCNU. The relationship between the O6-MT activity and the cellular resistance was almost linear, with relatively resistant cell lines exhibiting the higher levels of the O6-MT activity. This correlation between the O6-MT activity and the cellular resistance to nitrosoureas as ACNU and MCNU was not observed among other antitumour drugs, which included bleomycin (BLM), neocarzinostatin (NCS), cis-diamminedichloroplatinum (II) (CDDP), and etoposide (VP-16) in clinical use for brain tumour chemotherapy. This indicates that O6-MT activity can be an indicator of cellular resistance to antitumour nitrosoureas in the chemotherapy of brain tumours.
Animals↗
Reappraisal of bronchial arterial infusion therapy for advanced lung cancer.
As preoperative adjuvant therapy for advanced lung cancer, bronchial arterial infusion (BAI) of a chemotherapeutic agent was administered to patients with stage IIIa and IIIb hilar lung cancer. The infusion modality was changed for each term, from a single drug infusion, to a two drug infusion and then a three drug infusion, and the combination of infused drugs was selected in accordance with cell types. A significant radiographic shrinkage was observed after BAI therapy by the single, two and three drug infusions, being noted as 40.7 per cent, 61.8 per cent and 83.9 per cent, respectively. The effect on squamous cell carcinoma was more prominent than on other cell types. Upon microscopic examination of the resected specimens, significant histo-pathological effects were observed in 57.7 per cent of the patients who received single or two drug infusions, while the rate increased to as high as 92.2 per cent in the patients who received the three drug infusion. The histological effects of BAI therapy were also most marked in squamous cell carcinoma. It is of special interest that 5 of the 10 patients who received the three drug infusion of Carboquone (CQ) + Mitomycin C (MMC) + Nimustine-HCL (ACNU) for squamous cell carcinoma, showed complete disappearance of viable cancer cells at the tumor site; something which was never observed after the single and two drug infusions. It was therefore concluded that BAI therapy for advanced lung cancer should be reappraised through the modification of infusion methods.
Adenocarcinoma↗
Correlation of an in vitro chemosensitivity test using [3H] incorporation with the response in case of human tumor chemotherapy.
We developed a method for performing in vitro drug testing using [3H] incorporation into a primary human tumor. The test was applied to specimens from 60 patients with advanced malignancies, mainly gastrointestinal cancers. Forty-six specimens had sufficient growth for the drug testing. Forty-seven per cent of the gastric cancer specimens and 67 per cent of those from patients with colorectal cancer demonstrated an in vitro chemosensitivity. Among 9 chemotherapeutic drugs tested, ara-C, 5-fluorouracil, and mitomycin C showed the high percentages of positive sensitivity for gastric cancer, whereas actinomycin D, carboquone, and nimustine hydrochloride were sensitive in case of colorectal cancer. Clinical responses were compared with the results of the test. In 46 drug assays, in vitro/in vivo drug responses correlated in 78 per cent, with a true-positive rate of 47 per cent and a true-negative rate of 94 per cent. This test appears to be a reliable indicator for the clinical response to the same chemotherapeutic drugs in cases of the malignant diseases seen clinically.
Adult↗