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PubMed1984

Radio-chemo-immunotherapy (CCNU plus levamisole) for treatment of metastatic brain tumors. A pilot study.

Thirty-one patients with metastatic brain tumors were treated with Radiotherapy (RT) and CCNU or with RT, CCNU and Levamisole (LMS) in a randomized clinical trial. Twenty-seven were evaluable. All patients were submitted to whole brain radiation (50 +/- 5 Gy) and CCNU (130 mg/m2 p.o. every 8 weeks). 15 also received Levamisole (2.5 mg/kg p.o. daily for 3 weeks in the first month, for 2 weeks in the second, and then once a week monthly until progression). Primary tumor was predominantly lung cancer (22/27) and brain lesions were generally multiple (24/27). The overall response rate was 35% in the RT plus CCNU treated group and 38% in the RT plus CCNU plus LMS treated group. The median survival time was similar and not statistically different in both groups (7 versus 6 months). No important side effects were observed either in the RT + CCNU or in the RT + CCNU + LMS treated groups. The absence of combined depression of T-cell levels and responsiveness of lymphocytes to mitogens suggests that thymus dependent immunity could be improved by LMS administration. However, such improvement had no impact on duration of survival in patients with metastatic brain tumors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1983

Therapeutic evaluation of five nitrosoureas in a human melanoma xenograft system.

The development of nitrosoureas has switched from more lipophilic derivatives to congeners with higher water-solubility, since this property was presumably associated with a decrease in myelosuppression. We have compared the therapeutic efficacy of clinically well-known lipophilic nitrosoureas BCNU, CCNU, and MeCCNU with the recently introduced water-soluble nitrosoureas chlorozotocin (CZT) and hydroxyethyl-CNU (HeCNU), using a human melanoma xenograft system. There were considerable differences in tumor-inhibitory activity, with HeCNU ranking first and CZT last, and the rank order was similar for drug-induced lethality or bone marrow damage (in terms of reduced cellularity or macromolecular DNA damage). When the doses are expressed as percentages of the corresponding LD10/30 values, CZT ranks last and HeCNU low among conventional nitrosoureas. We conclude that water-solubility is not associated with reduced myelosuppression and that other guidelines will have to be adopted for rational development of nitrosoureas.

Animals↗
PubMed1983

Comparison of the transport of chlorozotocin and CCNU in L1210 leukemia and murine bone marrow cells in vitro.

The uptake of radiolabeled CLZ and CCNU by L1210 leukemia and murine bone marrow cells was investigated to determine whether the preferential ratio of alkylation of L1210 DNA to murine bone marrow DNA of 1.3 by 0.1 mM CLZ, as against a ratio of 0.6 by equimolar CCNU, is secondary to differences in uptake. The concentration of intact CLZ was determined in the medium and the intracellular water space. The cell: medium ratio (intracellular concentration/medium concentration) of CLZ in bone marrow cells was greater than that seen for L1210 cells. However, the intracellular CLZ concentration generally remained constant in both cell types at 37 degrees C, between 7.0 and 10.0 pmole/microliters. The L1210: murine bone marrow cell ratio of intracellular CLZ concentrations was approximately 1.0 from 10 to 60 min. The intracellular CCNU concentration during the uptake of 0.1 mM (chloroethyl-U-14C) CCNU at 37 degrees C was constant at 85 pmol/microliters from 10 to 60 min in L1210 cells, but slowly decreased from 66 pmole/microliters at 20 min to 43 pmole/microliters at 60 min in bone marrow cells. The L1210: murine bone marrow cell ratio of intracellular CCNU concentrations ranged from 1.45 to 1.98 from 20 to 60 min. Thus, it appears that the preferential ratio of alkylation of L1210 DNA to murine bone marrow DNA by CLZ compared with equimolar CCNU cannot be explained by differences in uptake of the two agents by the two cell types. The uptake of 0.1 mM CLZ at 37 degrees C by L1210 cells in McCoy's 5A medium containing 300 mg% glucose was not affected by the addition of 5 mM cold drug, nor was it affected by the absence of glucose in the medium, with or without cold drug. This suggests that CLZ uptake into L1210 cells is via passive diffusion and that CLZ does not enter these cells via the glucose transport mechanism.

Animals↗
PubMed1983

CCNU in combination chemotherapy for advanced histologically unfavorable non-Hodgkin's lymphoma.

During a 3-year period 39 evaluable patients with stage III and IV non-Hodgkin's lymphomas and unfavorable histologies were treated with a unique chemotherapeutic regimen based on a modified CHOP combination to which was added the nitrosourea, CCNU. Complete response was observed in six of 15 (40%) patients with diffuse poorly differentiated lymphocytic lymphoma (DPDL), four of 11 (36%) with diffuse mixed histiocytic lymphocytic (DML), and seven of 13 (54%) with diffuse histiocytic lymphoma (DHL). Of the 17 patients who achieved complete response, nine (53%) have remained continuously disease-free for greater than 2.5 years (2.7-4.1 years) from the onset of therapy: four of six with DPDL, two of four with DML, and three of seven with DHL. Median survival was 18.9 months for all patients, 18.9 months for those with DPDL, 17.4 months for those with DML, and 9.7 months for those with DHL. The median survival has not been reached for patients who attained a complete response, and will exceed 3.3 years. Central nervous system relapse was observed in three patients. In general, toxicity was moderate and consisted primarily of leukopenia, nausea, vomiting, and neurotoxicity. There were no drug-related deaths. The addition of CCNU to a modified CHOP combination resulted in an effective, generally well-tolerated out-patient regimen. However, it did not appear to decrease the rate of CNS relapse or improve current treatment results observed with other adriamycin-containing regimens for similar patients.

Adolescent↗
PubMed1987

Studies on the mechanism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced hepatotoxicity. II. Biochemical and morphological characterization of the injury and its prevention by phenobarbital.

The present study characterizes the biochemical, morphological, and histological sites of CCNU-induced hepatotoxicity and investigates the effect of modifiers of drug metabolism on this toxicity. A single oral dose (100 mg/kg) of CCNU caused four- and ninefold increases in serum GOT and GPT respectively 48 h after administration in rats. A 25-fold rise in serum bilirubin, a total loss of bile flow, and a decrease in BSP clearance were also observed. Cytochrome P-450 content and EM-N-demethylase activity were significantly decreased to 88% and 66% of control values respectively. A histopathological time course study of CCNU-induced injury showed a progression of acute inflammation, edema, and fibrin deposition in portal areas over 24 h with necrosis and sloughing of bile duct epithelium at 24 and 36 h. Treatment of rats with PB (40 mg/kg/day for 4 days, i.p.) 24 h prior to CCNU administration protected against CCNU-induced hepatotoxicity. Thus, the levels of serum GOT, GPT, and bilirubin were only 2.5 and 4 times higher than in untreated or PB-treated controls. Histopathological examination also showed reduced severity of bile duct lesions in PB-pretreated animals. In rats receiving both PB and CCNU, bile flow was restored and BSP clearance was increased compared to the CCNU-treated rats. The mixed-function oxidase activity in PB + CCNU-treated rats was not significantly different from that in PB-treated controls. It is concluded that pretreatment of rats with PB can markedly suppress the hepatotoxic manifestations, including histopathological changes, the rise in serum bilirubin, and the cholestasis observed in CCNU-treated rats.

Alanine Transaminase↗
PubMed1987

Studies on the mechanism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced hepatotoxicity. III. Ultrastructural characterization of bile duct injury.

The antineoplastic nitrosourea CCNU is a known hepatotoxin which has been shown to cause hyperbilirubinemia and reduction in bile flow. We studied morphological alterations in the common bile duct and interlobular bile ducts at 6, 12, and 24 h in male rats given a single oral dose (50 mg/kg) of CCNU. The portal vein was perfused with 1.0% glutaraldehyde fixative. Portal areas and the common bile duct were selectively dissected and processed using standard methods for light and transmission electron microscopy. The epithelial cells of larger common bile duct and interlobular bile ducts showed increased rough endoplasmic reticulum, markedly increased free ribosomes, and mitochondrial degeneration at 6 and 12 h after CCNU. There was also bile imbibition and loss of microvilli, which increased in severity at 12 and 24 h. The interstitium showed infiltration by acute inflammatory cells and dilated capillaries at 6 h. By 24 h, degeneration of epithelial cells was extensive; cells became necrotic and sloughed into the duct lumen. The smaller bile ductules showed no significant degenerative changes; adjacent hepatocytes were unremarkable. Early CCNU injury appears localized in the large bile ducts and reflects inflammatory edema, bile stasis, and degeneration of epithelial cells. Our studies suggest that this ductal injury may reflect metabolism of CCNU to reactive species within the bile ducts.

Animals↗
PubMed1980

Distribution of Bratton-Marshall-positive material in mice following intravenous injections of nitrosoureas.

As determined by a colorimetric assay measuring parent compounds plus ether-extractable nitroso-containing metabolites, N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) disappeared more rapidly than N-(2-chloroethyl)-N'cyclohexyl-N-nitrosourea (CCNU) and N-(2-chloroethyl)-N'-(4-transmethylcyclohexyl)-N-nitrosourea (MeCCNU) and their products from the tissues of mice injected IV. Assay of selected samples by high-pressure liquid chromatography revealed that the colorimetric assay for BCNU was specific in that the two assays gave equivalent results. Following IV-injections of CCNU and MeCCNU, however, levels of the parent compounds decreased much more rapidly than the total, color-producing material. Of seven tissues, the largest Cxt values for BCNU, as determined by the colorimetric assay, were noted for blood (442 microgram-min/ml) and large intestine (285 microgram-min/g). Liver (29 microgram-min/g) had the lowest Cxt value, reflecting rapid metabolism of the compound by this organ. Color-producing material related to CCNU disappeared from the solid tissues of mice in a manner generally parallel to that for blood. Of the Cxt values for this compound and its products, those for lung (1753 microgram-equivalents-min/g), kidney (1633 microgram-equivalents-min/g), and small intestine (1557 microgram-equivalents-min/g) were highest. Consistent with its slower rate of metabolism, MeCCNU and its color-producing metabolites remained in most tissues of mice for 12 h following injection. Except for brain (1434 microgram-equivalents-min/g), Cxt values for this nitrosourea and its metabolites in tissues were higher than those of blood (5485 microgram-equivalents-min/ml), with kidney (15,324 micrograms-equivalents-min/g), liver (12,921 microgram-equivalents-min/g), and large intestine (11,501 microgram-equivalents-min/g) being highest. For each nitrosourea, a fair correlation was observed between the Cxt values for tissues and the toxic and/or antitumor effects at those sites.

Animals↗
PubMed1986

CB 1954 revisited. II. Toxicity and antitumour activity.

We have assessed the antitumour activity of the nitrophenylaziridine CB 1954 in vitro and in vivo. For EMT6 mouse mammary tumour multicellular spheroids under hypoxic conditions in vitro, a 6-h exposure to 40 micrograms/ml reduced the surviving fraction to as low as 10(-3) and the growth delay was 5.4 days. Oxic cells were twofold less sensitive. Phenyl AIC protected oxic and hypoxic cells equally. Under oxic conditions minimal cell killing was seen with HT29 cells, either in multicellular spheroids or in monolayer; a 6-h exposure to 40 micrograms/ml gave a spheroid growth delay of 1.5-1.7 days. No growth delay was seen with single maximum tolerated doses of CB 1954 against HT29 grown as a xenograft in immunosuppressed mice. Only minimal growth delays of 1-2 days were seen with similar doses against the EMT6 tumour and the RIF-1 and KHT sarcomas in mice. Little activity was seen with maximum tolerated doses given once a day for 5 days against EMT6 and RIF-1. No chemosensitization was measurable with CCNU, cyclophosphamide or melphalan in the KHT tumour.

Animals↗
PubMed1984

Cyclic alternating combination chemotherapy for small cell lung cancer.

Sixty-two patients with small cell carcinoma of lung received cyclic alternating non-cross-resistant combination chemotherapy. Radiation to the chest was given to all the patients. Patients were given a course of VP16, adriamycin and vincristine (VAV) followed by radiation (3,000 rads) to the chest and then a second course of VAV. Three weeks later, a course of cytoxan, CCNU, and methotrexate (CCM) was given (6 weeks). Subsequently, the treatment was cycled between two courses of VAV (6 weeks) and one course of CCM (6 weeks). Overall objective response rate of 73%, with 45% complete response, was noted. Overall median survival was 50 weeks, with 83 weeks for complete responders. Median survival for patients with regional disease was 58 weeks compared to 40 weeks for extensive disease. All the patients headed for complete response did so prior to receiving CCM. These results were not superior to conventional combination chemotherapy regimens.

Adult↗
PubMed1986

Effects of sodium cyanate in mice bearing B16 melanoma.

Sodium cyanate injected IP at a dose level of 200 or 250 mg/kg caused a 90% or greater inhibition of the incorporation of [3H]thymidine into DNA of B16 melanoma transplanted SC in mice. Despite the inhibitory effect of sodium cyanate on precursor incorporation into DNA, no significant effect on host survival was observed when sodium cyanate was administered as a single agent in the diet, in drinking water, or by IP injection to mice that had received IP transplants of B16 melanoma. The action of melphalan and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in prolonging the survival time of melanoma-bearing mice was not enhanced by combined treatment with sodium cyanate. However, combined injections of sodium cyanate and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) increased the survival of tumor-bearing mice significantly more than injections of BCNU alone at a lower dose than the maximum tolerated one. These data and other studies suggest that B16 melanoma may be less responsive to the action of sodium cyanate than are murine leukemic cells or rat hepatomas.

Animals↗
PubMed1984

Potentiation by amphotericin B of the cytotoxicity of anticancer agents against MOPC-315 plasmacytoma and Lewis lung carcinoma.

The ability of amphotericin B (AmB) to potentiate the cytotoxicity of several different anticancer agents against two murine tumor models was examined. A spleen colony assay was used to quantitate the cytotoxicity of BCNU, CCNU, and L-PAM, either alone or in combination with AmB against the MOPC-315 plasmacytoma. A high level of potentiation of the effects of CCNU and L-PAM by AmB occurred, but AmB did not increase the cytotoxicity of BCNU. Tumor growth curves and calculation of cell survival demonstrated significant potentiation of the cytotoxicity of CCNU by AmB against SC Lewis lung carcinoma.

Amphotericin B↗
PubMed1978

Relationship of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) pharmacokinetics of uptake, distribution, and tissue/plasma partitioning in rat organs and intracerebral tumors.

To obtain a clearer definition of the relationship between the structure of BCNU and CCNU and their antitumor activity, we determined the uptake, distribution, and tissue/plasma partition ratios of both compounds in normal organs and intracerebral (ic) 9L tumors in rats. Greater uptake, distribution, and tissue/plasma partition ratios were obtained for parent CCNU in fat, liver, and brain, and for parent BCNU in kidney. CCNU distributes more rapidly and extensively than BCNU only in fatty tissues. BCNU distributed more extensively in kidney and liver. Rats received bolus IV injections of 14C-labeled BCNU or CCNU in increasing doses; measurements taken 30 min after injection showed that three- to fourfold more BCNU than CCNU was bound to nucleic acids in brain and ic 9L tumor tissue. Because the chloroethyl group is the alkylating moiety for both drugs, these findings implied that BCNU biotransformed to its reactive intermediate more rapidly than did CCNU. These observations, together with previous findings, indicate that one reason for the greater effectiveness of BCNU than CCNU against ic 9L tumors is its superior ability to form an intermediate that can bind to ic 9L tumor cell nucleic acids.

Animals↗
PubMed1988

The hepatotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats. Ultrastructural evidence of a delayed microtubular toxicity.

A few cases of liver involvement have been reported in patients receiving treatment with the antineoplastic nitrosourea CCNU. A single oral dose of 20 or 50 mg/kg CCNU in female Wistar rats induced an important increase in transaminases between day 2 and day 6, followed by a second, moderate increase between day 21 and day 28. Alkaline phosphatases and conjugated hyperbilirubinemia (threefold-increase) were noted for the two doses and were greater for the highest dose. Histological and ultrastructural studies disclosed hepatic lesions of two types: during the first phase of transaminase increase, inflammation of the portal tracts; during the second phase marked dilation of bile canaliculi and numerous filamentous bundles distributed at random throughout the liver cell cytoplasm like normal microtubules. Thus, CCNU induced pericholangitis and intrahepatic cholestasis with microtubular abnormalities. The long-term evolution of hepatic alterations revealed that in the 3rd month after a single oral dose of 20 mg/kg CCNU, lesions were persistent but stable; no reversibility was observed in the 3rd month after 50 mg/kg CCNU, and evolution towards cholangiolysis and biliary cirrhosis was noted. We suggest that CCNU causes a bimodal hepatotoxicity in rats: an early and prolonged ductal injury and a delayed anti-liver cell microtubule toxicity.

Alanine Transaminase↗
PubMed1985

Combination chemotherapy of advanced renal cell cancer with CCNU and vinblastine.

No remission was achieved in 15 evaluable patients with measurable metastatic renal cancer treated with CCNU 120 mg/m2 (day 1) and vinblastine 0.1 mg/kg body weight (days 1 and 8) repeated every 6th week. Two additional patients were not evaluable for response owing to early death from progressive disease. Previously reported beneficial response rates in metastatic renal cancer after treatment with CCNU and vinblastine could not be confirmed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

The effect of a novel taurine nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulfonyl)ethyl]-1-nitrosour ea (TCNU) on cytotoxicity, DNA crosslinking and glutathione reductase in lung carcinoma cell lines.

A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulfonyl)ethyl]-1-nitrosourea (TCNU) has been investigated with respect to cytotoxic mechanisms in rat and human cell lines which either possess (Mer+) or lack (Mer-) 0(6)-alkylguanine transferase activity. TCNU produced significantly greater cytotoxicity in the Mer- cells (Walker 256 rat breast carcinoma resistant to nitrogen mustards; human lung carcinoma A427) than in the Mer+ cells (Walker 256 wild-type; human lung carcinoma A594). This correlated with results generated by alkaline elution studies which showed that TCNU caused DNA interstrand crosslinks in A427 but not in A549 cells. Inhibition of glutathione reductase activity by TCNU demonstrated that in carbamoylating activity the drug was intermediate between chlorozotocin and 1,(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in both A427 and A549 cells. These data suggest that the presence of taurine in the drug structure does little to alter the cytotoxicity or the alkylating or carbamoylating properties of TCNU, and that any clinical advantages with TCNU will be the consequence of other factors.

Animals↗
PubMed1975

Bleomycin in testicular teratomas.

Bleomycin and its combinations have a definite place in the treatment of metastatic testicular carcinomas other than seminomas and may also prove to be effective, when given as adjuvant postoperative therapy in state II disease. A study, using the combination of Bleomycin and CCNU in 17 patients with metastatic testicular teratoma, is reported. A remission rate of 59% has been observed. Only patients with a complete remission had a satisfactory remission duration. Sequential combinations, using all drugs effective in this disease, may be the most promising way to further improve therapeutic results in terms of remission rate and survival.

Adult↗
PubMed1984

Non-Hodgkin lymphoma following Hodgkin's disease. A case report.

A 40-year-old male developed 66 months after diagnosis of Hodgkin's disease a non-Hodgkin lymphoma of high grade malignancy. Initially he had been treated by irradiation because of Hodgkin's disease PS IIA. After 2 years of remission he had relapsed and had received MOPP and CCNU. After 2 years without any therapy he developed the secondary neoplasm. With increasing frequency of long term survivors late complications, either therapy related or caused by immunologic defects, are observed.

Adult↗