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PubMed1977

Mechanism of uptake of nitrosoureas by L5178Y lymphoblasts in vitro.

The mechanism of uptake of nitrosoureas by L5178Y cells in vitro was investigated. A time course of the uptake of radioactivity on incubation of L5178Y lymphoblast with [14C]-1,3-bis(2-chloroethyl)-1-nitrosourea was linear for 30 min and then entered a plateau phase; it was markedly temperature dependent. A similar time course for cells incubated with [14C]ethylene-labeled 1-(2-chlorethyl)-3-cyclohexyl-1-nitrosourea reached equilibrium rapidly, was temperature independent, and resulted in a relatively low level of uptake of radioactivity. However, cells treated with 3-[cyclohexyl-14C]-1-(2-chlorethyl)-1-nitrosourea had a time course that was linear for 30 min, resulted in much higher levels of uptake of radioactivity, and was strongly temperature dependent. These findings, at least for 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, suggest that some drug decomposition precedes uptake. The percentage of radioactivity found in the cell sap fraction was at least 85% of total cell activity when cells were incubated with any of the three 14C-labeled nitrosoureas. Furthermore, thin-layer chromatography of the cell sap fraction revealed the presence of free intact drug. These findings indicate that intracellular uptake of intact nitrosoureas occurred. A time course of uptake of intact 1,3-bis(2-chloroethyl)-1-nitrosourea reached equilibrium rapidly with cell/medium distribution ratios of 0.2 to 0.6 and was temperature independent. The addition of excess unlabeled 1,3-bis(2-chlorethyl)-1-nitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea had no effect on uptake of [14C]-1,3-bis(2-chloroethyl)-1-nitrosourea, These findings suggest that uptake of intact 1,3-bis(2-chloroethyl)-1-nitrosourea was by passive diffusion. A time course of the uptake of intact 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with either [14C]ethylene- or ring-labeled drug rapidly reached equilibrium, was temperature independent, and attained a cell/medium ratio greater than unity. Uptake of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea was sodium independent and was unaffected by the metabolic inhibitors (sodium fluoride, sodium cyanide, or 2,4-dinitrophenol) or by urea, a potential physiological competitor. Furthermore, addition of unlabeled 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or 1,3-bis(2-chlorethyl)-1-nitrosourea had no effect on uptake of labeled 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. These findings suggest that uptake of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea also occurs by passive diffusion.

Animals↗
PubMedDate not supplied

Bleomycin (NSC-125066) and CCNU (NSC-79037) in the combination chemotherapy of mopp-resistant hodgkin's disease.

Twenty-two patients with MOPP-resistant stage IVB Hodgkin's disease were treated with a combination of bleomycin and CCNU. The response rate in 18 patients surviving at least 1 month was 72% with 11 partial and two complete responses. The mean duration of response and survival in partial responders were 12.2 and 17.5 months respectively. The two complete responses resulted in survivals of 20 and 36 + months. Bleomycin toxicity contributed to two deaths, one pulmonary and and one hypotensive. Severe CCNU toxicity occurred after three of 82 administrations but there were no CCNU-related deaths. The majority of patients in the study tolerated the regimen without serious toxicity. Although highly effective in the temporary control of advanced resistant Hodgkin's disease, the program will hopefully be improved by the addition of longer-acting agents.

Adolescent↗
PubMed1977

Prophylactic cranial irradiation in small cell carcinoma of the lung. A randomized study.

Twenty-nine patients with small cell carcinoma of the lung and without evidence of brain metastasis were randomized into two treatment groups consisting of 14 patients who received prophylactic cranial irradiation (PCI) and 15 who received none (non-PCI). All patients were treated with irradiation of the primary lesion and concomitant chemotherapy. The response rate and median survival of the two groups were not significantly different: 93% and 7.2 months in the non-PCI; 86% and 9.8 months in the PCI; P larger than or equal to .05. Brain metastasis occurred in 0/14 patients in the PCI and 4/15 in the non-PCI (P less than or equal to .05) and was the cause of major neurologic disability in each. Although PCI did not improve response rate or survival, brain metastasis with its attendant neurologic complications was effectively prevented.

Adult↗
PubMed1978

Adjuvant chemotherapy with intraventricular methotrexate and CCNU after surgery and radiotherapy of medulloblastomas.

Seven patients were treated with a combination of intraventricular methotrexate (MTX) and oral CCNU after resection and whole CNS irradiation of medulloblastomas. 3 patients survived 3 or more years after the operation which is not different from reported series with postoperative radiotherapy only. Adjuvant chemotherapy is experimental and should be employed only in controlled studies. The inadequate bone marrow reserve after previous spinal irradiation is a major problem. Because of its delayed and unpredictable myelotoxicity, CCNU is in our experience not a suitable substance for adjuvant combination chemotherapy of medulloblastomas. No complication was observed with 81 intraventricular injections of MTX. It is a good agent and deserves further clinical trials in less myelotoxic combinations.

Brain Neoplasms↗
PubMed1977

Paraneoplastic syndrome in childhood.

The case of five-year old boy is reported who at the age of 18 months had successfully been operated upon for neuroblastoma and who had subsequently signs of cerebellar encephalopathy. The paraneoplastic conditions of childhood are discussed in connection with the reported case. Opsoclonus was not observed in the patient, and symptoms showed rapid improvement on methotrexate, carmustine and CCNU treatment. Six months later the child was free of neurological disturbances and only displayed a slight mental retardation (IQ: 88). Cytological alterations observed in the CSF during the cerebellar encephalopathy are described in detail. At present, 41 months after the operation the child is well and free of symptoms.

Brain Diseases↗
PubMed1984

Disappearance of antibodies to Factor VIII in a patient with acquired haemophilia and carcinoma of the pancreas during cytotoxic therapy with fluorouracil and CCNU.

An inhibitor to clotting factor VIII (anti-VIII:C) developed in a 70 year old woman with carcinoma of the pancreas three months after palliative by-pass surgery. A life-threatening sublingual haemorrhage was controlled by infusion of human factor VIII concentrate in high dosage. With the objective of reducing pancreatic tumour size, combination cytotoxic therapy with fluorouracil and CCNU was given. Reduction in the size of the tumour was associated with disappearance of anti-VIII:C, reappearance of normal quantities of clotting factor VIII (VIII:C) in the plasma and resolution of the bleeding tendency. The anti-VIII:C was characterised as being predominantly of the IgG4 sub-class with k light chains. In vitro and in vivo studies showed the inactivation of VIII:C by anti-VIII:C was markedly non-linear. Normal quantities of factor VIII coagulant antigen (VIII:CAg) were detected in the patient's plasma when VIII:C levels were negligible.

Adenocarcinoma↗
PubMed1984

Combination chemotherapy in squamous cell carcinoma of the lung.

Sixty patients with advanced squamous cell lung carcinoma were entered in a study comparing the effectiveness of BACON and CAP combination chemotherapy. The CAP regimen was superior to the BACON regimen in response rate (50% vs 33%), median survival time (36 vs 24 weeks), and median time to progression (25 vs 16 weeks). Median survival time for responders was longer in both treated groups than for nonresponders. Side effects were significant, but generally reversible. This study seems to indicate a role for the CAP combination (cyclophosphamide, adriamycin, cisplatinum) as treatment for patients with squamous cell lung carcinoma.

Adult↗
PubMed1984

Pulmonary blastoma: remission with chemotherapy.

A 59-year-old man with pulmonary blastoma, who had undergone right-sided pneumonectomy, had a relapse of the tumour 7 months later. Light-microscopic and ultrastructural studies were consistent with recurrence from the primary tumour. Cell kinetic studies revealed a high fraction of tumour cells in the S-phase. Complete remission of the recurrence was obtained within 16 days after initiation of combination chemotherapy consisting of CCNU, vincristine, VP-16 and cyclophosphamide.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Urinary metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea.

Urinary metabolites of ring 14C-labeled 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (Methyl CCNU) from rats have been isolated and characterized by high-performance liquid chromatography and mass spectrometry. About 44% of the cyclohexyl moiety of CCNU was excreted in 24 hr and included approximately 10% of the excreted dose as free amines and 40% as conjugates that could be converted to amines by hydrolysis. Amine composition of free base plus hydrolyzable conjugates was 55% hydroxycyclohexylamines (3-trans, 3-cis, 4-cis, and 4-trans) and 30% cyclohexylamine. This strongly supports previous studies which indicated that CCNU is largely hydroxylated in vivo as well as in vitro. Rats pretreated with phenobarbital excreted high relative amounts of cis-4-hydroxy derivatives (41%), again showing a high degree of correlation between in vitro and in vivo results. Treatment of urine with beta-glucuronidase gave no apparent increase in free amines. However, sulfatase was about 25% as effective as alkaline hydrolysis for releasing free amines from whole urine. Major urinary metabolites were found to have m.w. of about 629, 413, 329, and 243 and represented 55%, 20%, 20%, and 5% of total excreted 14C, respectively. It was concluded that the higher m.w. metabolites may be conjugates of peptides possibly derived from active site-directed inactivation of specific enzymes. Previous work has shown that enzymes such as chymotrypsin and glutathione reductase are inhibited by isocyanates in this manner. Hydroxylated metabolites of Methyl CCNU had a pattern similar to that of CCNU. The major free (12%) and conjugated amine (54%) metabolites of Methyl CCNU in the urine in decreasing order of quantity present were cis-3-hydroxy-trans-4-methylcyclohexylamine, trans-4-methylcyclohexylamine, trans-4-hydroxymethylcyclohexylamine, and trans-3-hydroxy-trans-4-methyl-cyclohexylamine.

Amines↗
PubMed1977

Chemotherapy of human nervous system tumors: influence on cerebrospinal fluid sterols.

The cerebrospinal fluid levels of cholesterol, desmosterol, and the ratio 100 D:C taken from a study of 59 patients are reported. The patients, who had tumors of the nervous system, underwent neurosurgery, radiotherapy, and chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea or 1-(2-chlororethyl)-3-cyclohexyl-1-nitrosourea. The relationships among the levels of these three parameters and the clinical and neuroradiologic evolution are discussed.

Adult↗
PubMedDate not supplied

[CCNU in the chemotherapy of tumours of the central nervous system (author's transl)].

This study concerns 59 patients with primary and metastatic tumors of the CNS. After surgery, each patients followed a therapeutic protocol requiring Radiotherapy (5500 Rads for 6 weeks) and antiblastic monochemotherapy with CCNU (130 MG/M2/D p.o. every 8 weeks). The results were evaluated according to Wilson's (1975) criteria of response to therapy. CCNU significantly improved the survival time in comparison to the data given for conventional treatment.

Adult↗
PubMed1980

[Chemotherapy of malignant solid tumors].

In the chemotherapy of malignant solid tumours, also in form of the adjuvant chemotherapy, the results to be yielded are less favourable than in the diseases of the hemopoietic system. By a consequently performed poly-chemotherapy it is, nevertheless, possible to achieve remissions. By polychemotherapy we achieved in 13 metastatasized carcinomas of the mamma 4 partial and one complete remission, in 15 inoperable lung tumours we achieved four times a standstill of the growth and a complete remission over two years, whereas the tumours of the gastro-intestinal tract could be influenced less clearly. Treatments with only one medicament in each case were without any effect in solid epidermic tumours. The therapy is to be used effectfully only then, when indication, dosage and control of the patients are performed critically and exactly.

Bleomycin↗