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At least 199 records · Page 11Linked to original sources
PubMed1975

Combination chemotherapy with methyl-CCNU (NSC-95441), cyclophosphamide (NSC-26271), vincristine (NSC-67574), methotrexate (NSC-740), and bleomycin (NSC-125066) in advanced bronchogenic carcinoma.

Forty consecutive eligible patients with advanced bronchogenic carcinoma and no prior chemotherapy were treated with a 5-drug combination of methyl-CCNU, cyclophosphamide, methotrexate, vincristine, and bleomycin. Of the 36 patients who completed at least one 6-week course of treatment and were considered evaluable, 4 (11%) had partial tumor response. Response by cell type was as follows: 2(14%) of 14 patients with squamous cell carcinoma, 2(18%) of 11 with oat cell carcinoma, and none of 11 with adenocarcinoma. Toxicity in the group of 36 evaluable patients consisted of nausea and vomiting in 24 patients (67%), severe leukopenia (white blood cell count less than 1000 cells/-mm3) in 7 patients (19%), severe thrombocytopenia (platelet count less than 100,000 platelets/mm3) in 14 patients (39%), and bleomycin pulmonary toxicity in 2 patients (6%). This combination does not appear to be more effective than single-agent chemotherapy for bronchogenic carcinoma.

Adenocarcinoma↗
PubMed1978

The effect of combination chemotherapy on the reticuloendothelial system in man.

The effect of adjuvant combination chemotherapy (vincristine, CCNU/MeCCNU, 5-fluorouracil) on the phagocytic and catabolic properties of the reticuloendothelial system (RES) was studied in 4 patients before and during the anticancer treatment. The results indicate a transient impairment of both these functions, more prolonged with regard to phagocytosis. No significant changes were noted in the mobile macrophage system. This suggests that chemotherapy induces a depression especially of the stationary macrophage populations in the liver, spleen and bone-marrow.

Aged↗
PubMed1979

The effect of combination chemotherapy on neutrophil function in cancer patients.

The effect of adjuvant and palliative combination chemotherapy (Vincristine, MeCCNU, 5-Fluorouracil) on neutrophil function was studied in 18 patients prior to and during the anticancer treatment. Neutrophil responsiveness was assessed by leukocyte chemotaxis and chemiluminescence. No impairment could be observed in the circulating phagocyte function in either of the 2 groups before or in connection with short or long-term treatment.

Adult↗
PubMed1981

Mechanism of action of (2-haloethyl)nitrosoureas on DNA. Isolation and reactions of postulated 2-(alkylimino)-3-nitrosooxazolidine intermediates in the decomposition of 1,3-bis(2-chloroethyl)-, 1-(2-chloroethyl)-3-cyclohexyl-, and 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)-1-nitrosourea.

Three examples of the postulated but hitherto unisolated 2-(alkylimino)-3-nitrosooxazolidines (2) have been prepared containing cyclohexyl, trans-4-methylcyclohexyl, and 2-chloroethyl groups at the 2 position, respectively. These compounds correspond to intermediates previously postulated to be formed in the aqueous decomposition of the antitumor agents 1-(2-chloroethyl)-3-cyclohexyl- (CCNU), 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)- (MeCCNU), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), respectively, Compounds 2 decompose under physiological conditions to give a range of products similar to those formed from the corresponding (2-chloroethyl)nitrosoureas, including the hitherto unrecognized 2-hydroxyethl N-alkylcarbamates (9). Compounds 2a and 2b are converted with hydrochloric acid into CCNU and MeCCNU, respectively, suggesting that 2a and 2b may be reaction intermediates of decomposition. The corresponding 3-alkyl-1-nitroso-1-(2-hydroxyethyl)ureas (4) were characterized and, since they also decompose to give the same products as 2, may arise from the ring opening of 2. The intermediacy of compounds 4 can explain the formation of hydroxyethylated nucleosides isolated by other workers from the reaction of (2-chloroethyl)nitrosoureas on polynucleotides.

Alkylation↗
PubMed1978

Molecular structure of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea.

The three-dimensional structure of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU, NSC-95441), an effective antitumor agent, has been determined by single-crystal x-ray diffraction. MeCCNU crystallizes in monoclinic space group P21/c, with cell dimensions a = 12.387, b = 10.810, and c = 10 .198 A , beta = 102.62 degrees , and Z = four molecules per unit cell. The structure was solved by direct phasing procedures and refinement by anisotropic least squares converged at a discrepancy index R = 0.065. The cyclohexyl ring is in the chair conformation with the plane of the nitrosourea moiety twisted approximately 90 degrees from the cyclohexyl ring. The carbon-nitrogen bonds of the urea group are significantly asymmetric.

Chemical Phenomena↗
PubMed1977

Synthesis of analogues of N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea for evaluation as anticancer agents.

The superior activity of N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea (MeCCNU) against advanced murine Lewis lung carcinoma in comparisons with the cis form and other nitrosoureas prompted the synthesis of a number of MeCCNU analogues, including several cis-trans pairs. The methyl group was replaced by a variety of substituents (CO2H, CH2CO2H, CO2Me, CH2OAc, CH2Cl, OMe); the trans-3-methylcyclohexyl, cis-2-methyl-1,3-dithian-5-yl, cis- and trans-2-methyl-1,3-dithian-5-yl-tetraoxide, and 1-methylhexyl (open-chain) analogues were also prepared. Preliminary tests against murine leukemia L1210 revealed therapeutic indices (ED50/LD10) ranging from 0.26 to 0.79; all but three analogues effected 50% cure rates at nontoxic doses, the open-chain analogue being one of the least active. In terms of therapeutic index, diequatorial (trans-4) isomers were, with one exception, as active as or, in four of the eight examples, somewhat more active than the corresponding axial-equatorial (cis-4) isomers. In this series, four of the five 2-fluoroethyl analogues prepared were clearly inferior to the corresponding 2-chloroethyl analogues.

Animals↗
PubMed1984

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid, a nitrosourea with latent activity against an experimental solid tumor.

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid (N-Me-cis-CCCNU) was synthesized in five steps from cis-4-aminocyclohexanecarboxylic acid via an N-tosylated intermediate. N-Me-cis-CCCNU, which is incapable of the facile decomposition that characterizes the clinically useful nitrosoureas, effected a significant cure rate of both early and established murine Lewis lung carcinoma, even though its in vitro half-life was approximately 5.5 times that of the unmethylated parent compound. This is the first observation of latent activity of a nitrosourea against an experimental solid tumor.

Animals↗
PubMedDate not supplied

PALA versus streptozotocin, doxorubicin, and MeCCNU in the treatment of patients with advanced pancreatic carcinoma.

Seventy-three eligible, chemotherapy-naive, ambulatory patients with advanced pancreatic carcinoma were allocated to one of two treatment regimens: 35 received PALA (1250 mg/m2 daily x 5 every 4 weeks) and 38 were given SAM (streptozotocin 400 mg/m2 i.v. daily x 5, doxorubicin 45 mg/m2 i.v. on day 1 and 22, and methyl CCNU 60 mg/m2 orally on days 1 and 22 every 6 weeks). Doses were modified for myelo-, gi-, or cardiotoxicity. Adequate organ, bone marrow and cardiac function; a measurable lesion; adequate caloric intake; and a life expectancy of 2 months were required for treatment on this trial. One patient on each regimen had a partial response for response rates of 3% (95% confidence intervals, 0.08 to 17%). Median survival on the PALA arm was 5 months and median time to treatment failure was 2.6 months. SAM patients experienced median overall and progression free survivals of 3.4 and 1.9 months, respectively. The severe toxicity observed was almost exclusively myelosuppression on both regimens. One patient receiving SAM had lethal leukopenic sepsis during the first cycle as the only treatment-related death. Neither PALA nor SAM offer any therapeutic utility to patients with advanced pancreatic cancer.

Adult↗
PubMed1978

Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion.

Concentrations of 5-fluorouracil (FU) were measured in the plasma of patients receiving i.v. infusions of the drug for 5 days as treatment for adenocarcinoma of the gastrointestinal tract. Concentrations of FU varied widely in many patients. Concentration of drug X time of infusion (C X t values) were calculated. Patients showing a partial response or stabilization of disease had significantly higher C X t values than non-responders. Methyl CCNU did not affect the C X t values of FU. Determination of the plasma concentration of FU would allow the dose of the drug to be adjusted to maintain high concentrations of FU in the plasma. Our data suggest that such high concentrations would increase the response rate in this disease.

Adenocarcinoma↗
PubMed1980

In vitro chemosensitivity tests on xenografted human melanomas.

An in vitro chemosensitivity test has been applied to malignant melanoma cells from 5 patients. The tumour cells were first grown as xenografts in immune-suppressed mice, so that the results of the in vitro test could be compared with precise measurements of the sensitivity of the melanoma cells when exposed to chemotherapeutic drugs in vivo in the mouse. The in vitro assay involved exposing the tumour cells to each of 8 drugs, after which cell survival was determined by colony assay in soft agar. Dose-response curves were obtained and the surviving fraction at drug levels estimated to be achieved in man was used as a measure of in vitro drug sensitivity. Significant differences among the 8 drugs were detected, and these accorded with clinical experience. The correlation of in vivo (in the mouse) and in vitro sensitivities to Melphalan and MeCCNU was also significant.

Animals↗
PubMed1984

Identification of a subpopulation of MeCCNU resistant cells in previously untreated Lewis lung tumours.

A variety of experimental endpoints including excision cell survival, lung colony curability, tumour regrowth delay and i.m. tumour curability following MeCCNU alone and combined with gamma-radiation, were used to define the MeCCNU cell survival curve down to "tumour cure" level in previously untreated i.m. Lewis lung tumours. The survival curve was found to be biphasic, the tumour cells being markedly resistant to MeCCNU at high doses of the drug. Below 10 mg kg-1 the survival curve was exponential through the origin with a D10 of approximately 2 mg kg-1, while above 15 mg kg-1 the D10 was approximately 25 mg kg-1. From linear extrapolation of the terminal part of the cell survival curve to zero drug dose, it appeared that about 1 in 10(5) (or 0.001%) of tumour cells were resistant to MeCCNU.

Animals↗