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PubMed1979

Clinical results of autotransplantation after nitrosourea therapy.

Bone marrow harvested from two previously treated patients was cryopreserved prior to their first dose of Methyl CCNU. The thawed bone marrow was reinfused 96 hours after a subsequent dose of MeCCNU in one patient after the previous dose caused severe myelosuppression. In the other patient, the bone marrow was given 96 hours after an escalation of the MeCCNU dose. In both patients, myelosuppression was abrogated and viable stem cells were recovered in the peripheral blood.

Adenocarcinoma↗
PubMed1985

Effects of buthionine sulfoximine on the nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU).

Administration of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1 1-nitrosourea (MeCCNU; 50-500 mg/kg) to male F344 rats caused a time- and dose-related decrease of glutathione (GSH) preferentially in the liver, but not in the kidney. A 500-mg/kg dose of MeCCNU decreased liver, lung and kidney GSH by 69, 15 and 3%, respectively, 2 hr after dosing. However, MeCCNU had no effect on the ratio of GSH/oxidized GSH or on GSH reductase activity in any tissue tested. A single i.p. dose of DL-buthionine-SR-sulfoximine, an inhibitor of GSH biosynthesis, caused tissue GSH levels to decrease at a rate which reflected the biological half-life of GSH in the respective organs. The T 1/2 for GSH in kidney, liver and lung was found to be 1.5, 5 and 9 hr, respectively. MeCCNU administered s.c. to DL-buthionine-SR-sulfoximine-pretreated rats resulted in a depletion of hepatic and renal GSH concentrations which was additive to the effects of either of these treatments alone. DL-Buthionine-SR-sulfoximine also markedly increased the nephrotoxicity of MeCCNU and resulted in a hepatotoxicity not ordinarily seen when MeCCNU was administered alone. These results suggest that a reactive electrophilic intermediate may be involved in the mechanism of MeCCNU nephrotoxicity. Moreover, that renal GSH may play a protective role against MeCCNU-induced nephrotoxicity.

Animals↗
PubMed1985

Adjuvant therapy in rectal cancer: a protocol proposal.

The use of adjuvant radiation therapy and chemotherapy diminishes the likelihood of local-regional and distant recurrences and appears to prolong survival in patients who have undergone a complete surgical resection of a Dukes-Kirklin stage B2 or C rectal cancer. Patients with this malignant condition rarely develop peritoneal recurrences and therefore do not seem to be an appropriate group in which to evaluate the efficacy of intraperitoneal chemotherapy in gastrointestinal cancer. Such individuals, however, might serve as ideal subjects to examine objectively the merits of prolonged, ambulatory infusional chemotherapy through a prospective clinical trial comparing postoperative radiation therapy combined with 5-FU given in either protracted continuous infusional or intermittent bolus schedules.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1979

Synthesis and identification of products derived from the metabolism of the carcinostatic 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea by rat liver microsomes.

Liver microsomal metabolism of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea in the presence of reduced nicotinamide adenine dinucleotide phosphate and O2 was shown to produce seven metabolites that included the parent urea. A cytochrome P-450-dependent monohydroxylation of the cyclohexyl ring occurred in 3 positions, cis-3, trans-3, and cis-4, and on the methyl group to form a trans-4-hydroxymethyl derivative. In addition, monohydroxylation of the 2-chloroethyl carbon attached to the N-1 urea nitrogen yielded an alpha-hydroxy metabolite. A ring-hydroxylated derivative remained unidentified while the structures of all other such derivatives were established by comparison with compound synthesized, purified by high-pressure liquid chromatography, and characterized by mass spectral and nuclear magnetic resonance analyses. It was tentatively concluded that some parent urea is formed by a cytochrome P-450 dependent reaction because of a requirement for reduced nicotinamide adenine dinucleotide phosphate and inhibition by CO. Microsomes from rats pretreated with phenobarbital showed about a 3-fold increase in hydroxylation rate while phenobarbital-treated mice microsomes were induced 8-fold. However, in both species, the induced hydroxylation rate was about 4 nmol/min/mg protein. When microsomes from phenobarbital-induced rats were used, a mixture of 80% CO:20% O2 decreased the rate of formation of all metabolites to 14% of that in 80% N2:20% O2.

Animals↗
PubMed1979

Effects of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, and L-phenylalanine mustard on B16, Cloudman S91, and Harding-Passey mouse melanomas.

The effects of 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), and L-phenylalanine mustard (L-PAM) have been compared by using three i.p. transplanted mouse melanomas: the B16 melanoma in C57BL/6 mice; the Harding-Passey (HP) malanoma in BALB/c X DBA/2F1 (hereafter called CD2F1) mice; and the Cloudman S91 melanoma in DBA/2 mice. HP melanoma responds well to all three drugs. S91 responds only to L-PAM and MeCCNU. DTIC may accelerate death in mice bearing this tumor. B16 responds well to L-PAM and moderately well to MeCCNU and to multiple injections of DTIC. The best response to DTIC and MeCCNU is given by HP, while the best response to L-PAM is given by S91. Tumor cell-doubling times were found to be 1.5 days for B16, 2 DAYS FOR HP, and 3 days for S91. HP would seem to be the most responsive malanmoma with respect to the 3 agents studied. This may be due to an interaction between the chemotherapeutic agents and the host immune response, since the HP tumor arose in a noninbred mouse and is thus nonsyngeneic with the CD2F1 host. All three tumors appear to be interesting biological models for studying drug combinations and combined therapeutic modalities against melanoma.

Animals↗
PubMed1979

Chemotherapy for sarcoma of the stomach.

The results of chemotherapy for patients with advanced leiomyosarcoma of gastric origin were analyzed. A total of 23 single-agent and multi-drug regimens were given to 17 patients. DTIC and adriamycin (ADR) were the most commonly used chemotherapeutic agents. ADR was used alone or in combination in 13 patients, resulting in partial responses in two patients and disease stabilization in seven. One of the partial responses was obtained with the ADR-DTIC combination and the other was obtained with the cyclophosphamide-vincristine-ADR-DTIC combination. The survival duration for the responders was significantly longer than that obtained for those patients who had disease stabilization or progression. The results of the study show that leiomyosarcoma of gastric origin is less sensitive to chemotherapeutic agents than leiomyosarcomas of other sites, as reported in the literature. New approaches based on the natural history of the disease and with potential to improve the results of treatment of gastrointestinal sarcomas are indicated.

Adult↗
PubMed1979

Phase II study of 5-fluorouracil, methyl-CCNU, and daunorubicin in colorectal cancer: a Cancer and Leukemia Group B study.

The three-drug combination of 5-fluorouracil, methyl-CCNU, and daunorubicin was evaluated in 38 patients with unresectable or metastatic carcinoma of the colon. There were five partial responses and one complete response for an overall response rate of 16%. Although toxicity was tolerable, daunorubicin failed to add to the 5-fluorouracil and methyl-CCNU combination.

Adenocarcinoma↗
PubMed1979

Phase II evaluation of diglycoaldehyde, VP-16-213, and the combination of methyl-CCNU and beta-2'-deoxythioguanosine in previously treated patients with colorectal cancer: an Eastern Cooperative Oncology Group study (EST-1275).

The Eastern Cooperative Oncology Group assessed the activity of diglycoaldehyde (DGA), VP-16-213, and the combination of methyl-CCNU and beta-2'-deoxythioguanosine in previously treated patients with advanced colorectal cancer. Objective responses were seen in two of 40 evaluable patients receiving methyl-CCNU and beta-2'-deoxythioguanosine and in one of 35 patients receiving DGA. None of 33 patients responded to VP-16-213, but one death related to sepsis and bone marrow failure occurred. Survival of patients whose previous chemotherapy included a nitrosourea was markedly shortened compared to those who had not been exposed to nitrosoureas. With the possible exception of DGA, further treatment of patients with colorectal cancer with these therapies is not warranted.

Aldehydes↗
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↗