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At least 1,423 records · Page 79Linked to original sources
PubMed1988

Sensitization of nitrosourea-resistant Mer+ human tumor cells to N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea by mild (41 degrees C) hyperthermia.

Experiments were designed to determine whether heat treatment could sensitize nitrosourea-resistant human tumor cell lines expressing a repair system (O6-alkylguanine DNA alkyltransferase; Mer+) capable of removing monoadducts from the DNA of treated cells prior to the formation of lethal interstrand cross-links. Effects of temperatures compatible with systemic hyperthermia were of particular interest, and, consequently, the effect of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) exposure in vitro for 4 h at 37 degrees C was compared with that for 1 h at 41 degrees C followed by 3 h at 37 degrees C. CCNU toxicity was significantly enhanced by heat treatment in the Mer+ HT-29 human colon carcinoma, and in HeLa-S3 and HeLa-CCL2 cell lines [thermal enhancement factor (ratio of CCNU doses required to reduce cell survival to 0.001 at 37 degrees C and 41 degrees C) = 1.3-1.4]. Pharmacokinetic studies indicated that the effect of heat treatment on CCNU toxicity was not attributable to exposure to increased concentrations of reactive species, nor was the enhancement due to a direct effect of heat and/or drug on alkyltransferase activity. A similar enhancement of CCNU toxicity was also observed in a Mer- line, HeLa-MR (thermal enhancement factor = 1.3). Heat-sequencing experiments clearly demonstrate that heat and CCNU must be administered concurrently. Alkaline elution experiments were designed to examine DNA-DNA cross-link formation in Mer+ and Mer- cells exposed to CCNU at 37 degrees C and 41 degrees C, but quantitation of cross-link formation was not possible owing to the persistence of single strand breaks in the DNA of drug-treated cells. Nevertheless, collectively the data indicate that thermal enhancement of CCNU toxicity is independent of effects on alkytransferase activity and indicate that hyperthermia could provide an effective strategy for improving the nitrosourea response of resistant Mer+ tumors.

DNA↗
PubMed1988

[Use of nitrosourea derivatives in the treatment of patients with Hodgkin's disease with lesions of the central nervous system].

The study deals with the effectiveness of nitrosourea derivatives (nitrosomethylurea and CCNU) used for monochemotherapy or polychemotherapy in combination with vinca alkaloids, natulan and prednisolone in 22 patients suffering Hodgkin's disease with spinal cord and intracranial involvement. Complete regression of neurologic symptoms was seen in 61.1% of patients with spinal cord dysfunction and in 3 of 4 cases of brain involvement. The effectiveness of nitrosomethylurea-based regimens did not differ-significantly from those including CCNU. The longest complete remission obtained was 124+ months. No relationship was found between the type, degree and duration of symptoms, on the one hand, and the likelihood of achieving complete remission, on the other.

Adolescent↗
PubMed1988

[Status of the heart during a combined method of treating patients with stage I to II lymphogranulomatosis].

The effects of combined therapy (polychemotherapy and radiotherapy) of 162 patients with stage I-II Hodgkin's disease were studied. A retrospective analysis of x-ray findings led to the detection of exudate in the pericardial cavity unrecognized in hospital in 7.7% of the patients. Combined therapy caused its reverse development into adhesive pericarditis. X-ray assessment of the cardiac state during a follow-up (3-5 yrs.) revealed various postradiation complications: limited pleuropericardial adhesions (17%), extensive pleuropericardial adhesions revealing the right spinal contour (12.7%), exudative pericarditis (0.7%), and adhesive pericarditis (12.7%). A low rate and degree of postradiation injuries of the pericardium could be accounted for by preliminary polychemotherapy making it possible to reduce radiation fields in subsequent irradiation.

Adult↗
PubMed1988

[Efficacy of the "8 drugs in a day" protocol in brain tumors in children].

In the present study, the "8 drugs in 1 day" regimen was tested in 54 children: 27 relapses (brain and/or spinal and/or meningeal sites), 10 refractory progressive diseases, 13 macroscopic residual tumors after partial excision and/or radiotherapy; in 4 cases, this regimen was prescribed as first line treatment. The response rate (complete and partial remission) was 46%. Results were very encouraging in medalloblastomas with a response rate of 76.5% whereas in brain stem gliomas it was only 23% and 33% in other astrocytomas. Immediate toxicity, mainly hematological, was very moderate. These results justify to propose this regimen as adjuvant chemotherapy, mostly in medulloblastomas and to plan other similar trials, using the most active drugs which seem presently to be alkylating and platinum-derived agents.

Adolescent↗
PubMed1987

[Abdominal metastasis of a pineal germinoma in a child with a ventriculo-peritoneal shunt].

We present a case of germinal tumor of the pineal gland, treated with a ventriculo-atrial shunt, cytostatics and radiotherapy. Two and a half years later, in Spite of the clinical remission of the cerebral tumor a metastasis appeared in the abdominal cavity. After reviewing the current literature, the necessity of using millipore filters in the CSF derivation systems when dealing with malignant cerebral tumors to avoid the spreading of malignant cells through the CSF.

Abdominal Neoplasms↗
PubMed1987

Haematotoxicity of doxorubicin and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and of their association in rats.

Doxorubicin is an anthracycline widely used in the treatment of leukaemias, lymphomas and solid tumors. Doxorubicin cannot pass into the cerebrospinal fluid. Nitrosoureas are known to be lipophilic and to be able to penetrate the blood-brain barrier. CCNU is a nitrosourea used to treat Hodgkin's disease, brain tumors and other solid tumors. The authors have previously reported on the nephrotoxicity and hepatotoxicity of these drugs; the present paper reports their findings on haematotoxicity in female Wistar rats. In one group 40 rats received 10 mg/kg doxorubicin. In a second group 40 rats received 20 mg/kg CCNU, and a further 40 rats received 50 mg/kg CCNU. In a third group 60 rats received the association doxorubicin 10 mg/kg plus CCNU 20 mg/kg. Blood counts were performed on days 4, 8, 15, 21 and 28 after treatment. Leucopenia and severe thrombocytopenia were noted after doxorubicin administration. A biphasic decrease in the leucocyte count was observed after CCNU treatment. More severe alterations were observed when doxorubicin and CCNU were combined. Very few data on haematological abnormalities following treatment of human patients have been published. Similarities can be seen between the haematological side-effects noted in rats and those occurring in humans treated with these cytotoxic drugs. Female Wistar rats seemed to be a good model to evaluate the haematological tolerance of anthracycline, nitrosoureas or of their association. If multiple courses of these drugs have to be administered, the evolution of haematological alterations must be known: the decrease phase of blood cells is followed by a rebound phase. The drug should be avoided during this phase of granulocyte activation.

Animals↗
PubMed1987

[Value of initial chemotherapy in the treatment of advanced cancers of the uterine cervix].

Eleven patients who had advanced cancer of the cervix were treated with combination chemotherapy containing Cisplatin as a primary treatment. The cases were: 3 stage II B N+, 2 stage III not involving the bladder, 3 stage III involving the bladder and 3 stage IV. The response rate was 40% with 6 patients responding. The response was better than 50% in 3 and there were 5 failures. In the 6 patients where the treatment was helpful, 2 could have extended surgery whereas the others had follow-up radiotherapy without developing urinary fistulae. Just as it to be found in the literature, it was not possible to pick out prognostic criteria for sensitivity to chemotherapy. A protocol for treatment is suggested, starting with a therapeutic test of chemotherapy. If this is successful it should be followed by extended surgery or radiotherapy. It if is not successful, conventional treatment with radiotherapy will be undertaken. It is essential to carry out multicentre studies in future to find out whether this attitude is going to be successful.

Adult↗
PubMed1987

Improved delivery through biological membranes. XXX. Synthesis and biological aspects of a 1,4-dihydropyridine based chemical delivery system for brain-sustained delivery of hydroxy CCNU.

A redox chemical delivery system based on the NADH in equilibrium NAD+ model was applied to an active metabolite (D) of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), i.e. CCNU-OH. The 1,4-dihydrotrigonelline ester of CCNU-OH, N-(2-chloro ethyl)-N'-[trans-4-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)cyc lohexyl]- N-nitrosourea (D-CDS) was prepared by a direct hydride transfer reaction of the corresponding pyridinium precursor (D-Q+) with a highly reactive 1-benzyl-1,2-dihydroisonicotinamide. The in vitro kinetics in biological fluids indicated facile oxidative conversion of D-CDS to D-Q+. An in vivo study showed that one intravenous injection to rats of D-CDS resulted in rapid brain accumulation of D-Q+, followed by a sustained release of CCNU-OH, while D-Q+ was rapidly eliminated from systemic circulation. The ratio of brain/blood concentration of D-Q+ was found to increase progressively with time. At an equimolar dose of CCNU-OH, the ratio of brain/blood concentration for CCNU-OH was found to be close to unity.

Animals↗
PubMed1986

Two mechanisms of synergism when amphotericin B is used in combination with actinomycin D or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea against the human promyelocytic leukemia cell line HL-60.

The toxic effects of the combinations of amphotericin B (AmB) and actinomycin D or AmB and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea were measured against the human promyelocytic leukemia cells HL-60. The toxicities of both drug combinations were greater than the additive toxicity of each of the drugs used singly, but the exact conditions under which synergism was achieved differed for each combination. The synergism achieved by the AmB-actinomycin combination was accompanied by an AmB-induced increase in uptake of actinomycin D by the HL-60 cells, whereas the synergism of the AmB-1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea combination could be linked to potentiation by 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea of AmB-induced oxidative injury. These results indicate that the synergism of these two drug combinations was caused by different mechanisms.

Amphotericin B↗
PubMed1978

Autologous bone marrow grafts in dogs treated with lethal doses of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

Hematological and immunosuppressive effects of various single doses of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) were evaluated in the preclinical canine model. Immune function appeared not to be impaired by treatment with CCNU, but severe myelotoxicity contributed to the death of 3 of 4 dogs given 10 mg CCNU per kg and 5 of 5 dogs given 15 mg CCNU per kg within 10 days after drug administration. Infusions of autologous bone marrow protected 6 of 6 dogs receiving 15 mg CCNU per kg and 6 of 6 dogs receiving 20 mg CCNU per kg from lethal marrow failure. Dogs given 30 mg CCNU per kg and autologous marrow died within 7 days from severe gastrointestinal toxicity. We conclude that autologous bone marrow support may allow the use of high-dose CCNU regimens and thereby increase its therapeutic efficacy in the treatment of advanced cancer.

Animals↗
PubMed1986

Chemotherapy for soft tissue sarcoma.

Adriamycin is the only active single agent for patients with metastatic sarcoma; combination chemotherapy regimens that omit Adriamycin are ineffective in adults. Despite early success with CYVADIC, there have been recent doubts regarding its efficacy. No other chemotherapeutic combination has provided consistently better results than CYVADIC. As complete responses occur in less than 15 per cent of patients there is a need for further evaluation of new regimens. It is necessary to evaluate new regimens in prospective, randomized studies. Response criteria should be consistent and reproducible. Attenuation schedules and data relating to the total administered dosage should be provided. It would also be beneficial to analyze prognostic variables so that patients liable to an unfavorable outcome could be identified before commencement of treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

[Hepatotoxicity of (chloro-2-ethyl)-1-cyclohexyl-3-nitroso-1-urea (CCNU) in the rat].

Few cases of liver involvement have been reported in patients receiving treatment with CCNU. CCNU is an anti-tumoral agent used in the treatment of leukemia, Hodgkin's disease and bronchial or cerebral tumors. A single daily dose of 20 or 50 mg/kg CCNU in female Wistar rats induces an important increase of transaminases, reaching 10 times initial level between day 2 and day 6, followed by a second and moderate increase between day 21 and day 28. Three-fold increased alkaline phosphatases and conjugated hyperbilirubinemia were noted for the two doses, and was greater for the higher dose. Histological and ultrastructural studies showed two types of lesions: during the first phase of transaminase elevation, edema and inflammatory infiltration of the portal spaces; during the second phase of transaminases elevation, numerous bundles of pericanalicular microfilaments and severe dilation of the biliary tract. Hepatic cells had few alterations although some necrotic foci were observed, particularly at the higher dose. So CCNU induced an intrahepatic cholestasis with pericholangitis in the rat.

Alkaline Phosphatase↗
PubMed1986

Autologous marrow transplantation for patients with chronic myeloid leukemia in accelerated or blastic phase: report of 14 cases.

Between June 1979 and October 1983, 14 autografts were performed in 13 patients with CML (ten blast crisis, four accelerated phase). Results were disappointing: four patients died during aplasia; seven returned to chronic phase, but three died of hemorrhage, four relapsed, and three did not reverse. The main problem was the very low rate of successful engraftment. Both the collection of bone marrow after treatment with busulfan and a particular sensitivity of CFU-GM to cryoinjury were responsible for the infusion of very low doses of CFU-GM. However, we observed some promising results: In one patient in acute blast crisis, the Ph 1 chromosome disappeared, as well as the cytogenetic marker of transformation; in another patient with acute pure cytogenetic acceleration, the abnormal clone disappeared for 27 months; a third patient was maintained in a second chronic phase for 20 months. Thus we suggest that the results of autografting in chronic myeloid leukemia would be improved by infusing the largest possible dose of stem cells collected before or long after treatment by busulfan, and freezing them following a careful program.

Adult↗
PubMed1986

[Combination chemotherapy of disseminated skin melanoma with nitrosomethylurea].

Since 1971 the efficacy of a combination chemotherapy, which included the nitrosoalkylurea derivative nitrosomethylurea, was tested in three clinical trials. The combination of vincristine (VCR), nitrosomethylurea (NMM) and actinomycin-D (Act.-D) showed an activity of 34.9% (10.9% CR + 24% PR) with a duration of remission from 2 to 30 months in 92 patients. The comparison of the combination VCR, NMM, Act.-D (group 1 = 44 pat.), VCR, NMM, Act.-D, DTIC (group 2 = 46 pat.) and VCR, Act.-D, CCNU, DTIC (group 3 = 48 pat.) showed an efficacy (CR + PR) of 29.6%; 28.3% and 18.8%. The duration of remission within all three groups is significantly longer in patients with a CR. In the first and second group the survival after 12, 18 and 24 months is significantly better than in the third group. The median survival time of patients reaching CR is in the first and second group (30.4 and 28.7 months) significantly better than in the third group (20.5 months). The comparison of a DTIC-monotherapy (group 1 = 56 pat.) and the combination VCR, NMM, Act.-D. (group 2 = 58 pat.) showed 7.1% CR and 16.0% PR, and 13.7% CR and 10.4% PR respectively. A cross over, when a progression occurred, was ineffective; survival time being 6.9 and 6.5 months did not differ.

Antineoplastic Combined Chemotherapy Protocols↗