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PubMed1984

Possible factors in the potentiation of 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl-1-nitrosourea cytotoxicity by alpha-difluoromethylornithine in 9L rat brain tumor cells.

Depletion of intracellular levels of polyamines in 9L rat brain tumor cells by alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, significantly enhanced the cytotoxicity of 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl-1-nitrosourea (MeCCNU) in vitro as measured by a colony-forming efficiency assay. Administered as a single agent, DFMO was not cytotoxic to 9L cells. Treatment for 48 hr with 10, 1, 0.5 or 0.1 mM DFMO produced similar levels of polyamine depletion-and similar potentiation of MeCCNU cytotoxicity. Restoration of intracellular polyamine levels by the addition of exogenous putrescine (1 mM) to treated cells prevented the potentiation of MeCCNU, which indicates that this phenomenon might be the result of polyamine depletion. DNA adduct formation in polyamine-depleted and control cells was studied with [14C]-MeCCNU; no difference in monoadduct formation was found between polyamine-depleted and control cells. Experiments to determine whether polyamine depletion has an effect on enzymes involved in the repair of alkylated bases showed that the activity of O6-methylguanine-DNA demethylase, 7-methylguanine-DNA glycosylase and 3-methyladenine-DNA glycosylase were unaffected by 48 hr of treatment with 10 mM DFMO. DFMO treatment causes a substantial increase in the intracellular content of decarboxylated S-adenosyl-L-methionine, which was reversed by addition of putrescine. The possibility that the elevation of decarboxylated S-adenosyl-L-methionine rather than the depletion of polyamines is responsible for the effects of DFMO is discussed.

Animals↗
PubMed1987

Development of MeCCNU-resistance in clonally derived lines of Lewis lung carcinoma.

The development of resistance to MeCCNU in four clonal lines of Lewis lung carcinoma derived from lung colonies has been examined. Treatment of the clones with 15 mg/kg MeCCNU once in each in vivo passage resulted in a rapid reduction in tumour responsiveness to this drug. This shows that MeCCNU resistance can arise at rates which may be applicable in spontaneous tumours and their metastases. Karyotypic heterogeneity was evident very early after isolation of the clones and this has potentially important implications for the experimental use of clones and for the features of metastatic disease. Karyotype analysis of one of the clones at each passage suggested that development of resistance was associated with the selection of a single sub-population of tumour cells but the kinetics of resistance development cannot be totally explained in terms of this simple selection.

Animals↗
PubMed1984

Studies on drug resistance in a human melanoma xenograft system.

Alkylating agents and their functional analogues belong to the most useful antineoplastic drugs in the treatment of disseminated malignant melanoma. In conjunction with an open clinical phase II trial evaluating the combination of cisplatin and ifosfamide, 17 melanoma xenograft lines were established from patients often refractory to dacarbazine (DTIC). These xenograft lines were exposed to cisplatin, dacarbazine, dibromodulcitol, ifosfamide, methyl-CCNU, mitomycin C, and malonato-diaminocyclohexane-platinum II (PHM) at the respective LD 10/30 doses. Growth delay values less than 2 corresponded in 26/27 instances with progressive disease, whereas values greater than 2 corresponded in only 10/13 instances with achievement of a no-change status or a partial remission of the donor patient's disease. Among the panel of DNA-damaging agents tested, cross-resistance was incomplete. Some xenograft lines revealed unique chemosensitivity patterns in contrast to a uniform pattern of drug resistance in others (pleiotropic or multidrug resistance). The data confirm independently of results obtained in the phase II study that the combination of cisplatin and ifosfamide is effective against malignant melanoma refractory to dacarbazine. Suboptimal drug exposure, repeated up to 21 transplant generations, was employed to induce secondary resistance to either dacarbazine, melphalan or methyl-CCNU in a melanoma xenograft line originally quite sensitive to drug treatment. When the resistant sublines were exposed to the other agents, only partial cross-resistance was observed. Tumour volume responses to treatment with dacarbazine correlated with persisting DNA damage assayed 24 h after in vivo drug exposure in a sensitive line and the absence of such lesions in a resistant line.

Animals↗
PubMed1984

Nitroimidazoles as modifiers of nitrosourea pharmacokinetics.

We have studied the effect of a number of nitroimidazole sensitizers of varying lipophilicity on the pharmacokinetics of CCNU in mice. It was found that the effectiveness of these compounds in producing pharmacokinetic effects correlated directly with their lipophilicity, viz. in the order: benznidazole (Benzo) greater than Ro07-1902 misonidazole greater than (MISO) greater than Ro05-9963. The effects of MISO on the pharmacokinetics of 4 nitrosoureas of differing lipophilicity were also investigated. The plasma clearances of CCNU, BCNU and MeCCNU (high lipophilicity) were slowed by MISO whereas that of chlorozotocin (Chlz) (low lipophilicity) was unaffected. Thus, it seems that for a pharmacokinetic interaction to occur between a nitroimidazole and a nitrosourea, both the modifier and the cytotoxic agent must have a requisite degree of lipophilicity. As the same requirement appears to hold for enhancement of tumor response, these data provide further evidence that pharmacokinetic modification plays a major role in chemosensitization.

Animals↗
PubMed1985

Combination chemo-radiotherapy for residual, recurrent or inoperable carcinoma of the rectum: E.C.O.G. study (EST 3276).

Thirty evaluated patients were randomized to either continuous radiation + 5-FU (16 patients), or split-course radiation + 5-FU (14 patients) for the treatment of residual, recurrent, or inoperable carcinoma of the rectum or recto-sigmoid. Twenty-one of these patients received maintenance MeCCNU + 5-FU chemotherapy following radiation. Entry was terminated when late treatment reactions were seen in the precursor pilot study. Twenty-four of the patients have died; the estimated median survival is 17 months in each of the treatment arms. Performance status was the only significant prognostic factor for survival. The rate of severe, acute reactions during the radiation treatment period was higher for the continuous-course than for the split-course regimen (69 vs. 21%, p = .01). The rates of severe late treatment reactions, 23% (7 of 30), and severe chemotherapy toxicity, 48%, were similar for the two treatment programs. Late treatment reactions, primarily bowel complications, were seen from 3 to 23 months after radiation in 3 patients treated with continuous course, and 4 patients treated with split course. Ten of 21 patients (48%) who received maintenance chemotherapy had severe or worse toxicity. Toxicity was seen for 6 of 12 continuous-course, and 4 of 9 split-course patients. Twenty-seven patients have had disease progression, and the median length of disease control is 11 months.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Comparison of DNA lesions produced by tumor-inhibitory 1,2-bis(sulfonyl)hydrazines and chloroethylnitrosoureas.

1,2-Bis(sulfonyl)hydrazine derivatives, designed to generate several of the electrophilic species classically believed to be responsible for the alkylating (chloroethylating) and/or carbamoylating activities of the chloroethylnitrosoureas (CNUs), were compared with respect to the cross-linking and nicking of T7 DNA to that caused by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and 1-(2-chloroethyl)-3-(4-trans-methylcyclohexyl)-1-nitrosourea (MeCCNU). In the case of BCNU, a large proportion of T7 DNA strand nicking was found to be due to the generation of 2-chloroethylamine, produced from the hydrolysis of 2-chloroethylisocyanate, in turn formed during the decomposition of the parental nitrosourea. 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (compound 1) gave a greater yield of DNA cross-links than the CNUs. Compound 1, as well as its derivatives that were incapable of generating 2-chloroethylisocyanate, did not produce detectable levels of strand nicking, indicating that N7-alkylation of guanine did not occur to a significant extent with these agents. Since compound 1 and its derivatives are believed to generate chloronium and chloroethyldiazonium ions, it would appear that these species could not be significantly involved in the N7-alkylation of guanine caused by the CNUs. The relatively low level of N7-alkylation of guanine residues and the relatively high yield of cross-links generated by some of the 1,2-bis(sulfonyl)-1-(2-chloroethyl)hydrazine derivatives implies that they are more exclusive O6-guanine chloroethylating agents than the CNUs. O6-Guanine chloroethylation is believed to be the therapeutically relevant event produced by the CNUs; therefore, compound 1 derivatives represent promising new cancer chemotherapeutic agents, since they appear to generate lower quantities of therapeutically unimportant, yet carcinogenic lesions, and more of the therapeutically relevant O6-guanine chloroethylation than the CNUs.

Antineoplastic Agents, Alkylating↗
PubMed1981

A comparison of hydroxyurea, methyl-chloroethyl-cyclohexy-nitrosourea and cyclophosphamide in patients with advanced carcinoma of the prostate.

This is the fifth completed randomized clinical trial of the National Prostatic Cancer Project. There were 125 patients with histologically confirmed relapsing clinical stage D prostatic cancer randomized to receive hydroxyurea, methyl-chloroethyl-cyclohexy-nitrosourea or cyclophosphamide. All patients had received and failed previous hormonal therapy. Patients whose disease progressed after 12 weeks on the initial therapy were crossed over or randomized to receive an alternate drug. There were 98 patients available for comparison of treatments. Objective responses included patients with complete or partial regression as well as stable disease. The response rates were 35 per cent for cyclophosphamide, 30 per cent for methyl-chloroethyl-cyclohexy-nitrosourea and 15 per cent for hydroxyurea. Subjective response parameters included improvement in performance status and relief of pain. Pain was improved in a fifth of the patients on each treatment area. Methyl-chloroethyl-cyclohexy-nitrosourea and hydroxyurea showed activity in advanced prostatic cancer patients but at the expense of excessive toxicity. Cyclophosphamide continues to be the most active single agent in this type of patient, particularly with regard to duration of response and survival. There was a statistically demonstrable advantage for cyclophosphamide over hydroxyurea and a marginal advantage over methyl-chloroethyl-cyclohexy-nitrosourea in survival experience.

Acid Phosphatase↗
PubMed2001

National Surgical Adjuvant Breast and Bowel Project trials in colon cancer.

During the last decade, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has completed six adjuvant chemotherapy trials comparing different adjuvant therapy regimens or adjuvant therapy versus surgery alone. A seventh trial is ongoing. These trials have contributed to defining the role of adjuvant therapy in colon cancer. Patients eligible for inclusion in NSABP trials had been diagnosed as having stage II or III colon cancer with no evidence of gross residual or metastatic disease. The follow-up strategies were similar in the reported trials with follow-up every 3 months for the first 2 years, then every 6 months for the next 3 to 5 years, and annually thereafter. The NSABP C-01 protocol was a three-arm trial comparing an adjuvant semustine/vincristine/5-fluorouracil (5-FU) regimen (MOF) to a Bacille Calmette-Guerin treatment, and to surgery alone. The C-02 protocol investigated whether portal vein infusion of 5-FU improved survival outcome compared with surgery alone. Protocol C-03 compared a semustine/vincristine/5-FU regimen to a 5-FU plus leucovorin (LV) (5-FU/LV) regimen. The NSABP C-04 protocol was a three-arm trial comparing 5-FU/LV, 5-FU plus levamisole, and 5-FU/LV plus levamisole. The NSABP C-05 trial compared 5-FU/LV to 5-FU/LV plus alpha-interferon. Results of NSABP C-01, C-02, C-03, C-04, and C-05 trials are summarized in this report. Patient accrual has completed in the NSABP C-06 trial comparing 5-FU/LV with oral tegafur and plus uracil leucovorin. The NSABP is currently conducting another trial (C-07) comparing 5-FU/LV with 5-FU/LV plus oxaliplatin. The role of adjuvant chemotherapy in stage II colon cancer is also discussed in this report. A recent pooled analysis of studies C-01, C-02, C-03, and C-04 has indicated that the relative treatment benefit in stage II disease is at least equal to the benefit in stage III colon cancers, and concluded that adjuvant chemotherapy also should be considered as the standard of care for stage II colon cancer patients.

Adjuvants, Immunologic↗
PubMed1988

L1210 leukemia hybrids isolated after fusion of alkylating agent-resistant sublines.

The two resistant lines, L1210/CPA (cyclophosphamide) and L1210/MeCCNU (1-(2-chloroethyl)-3-(trans-4-methyl-cyclohexyl)-1-nitrosourea) were used, each of which is not cross-resistant to the drug to which the other line is resistant. Their resistance was used as markers as well as the basis for selection of the hybrids. For the production of hybrids five in-vivo or in-vitro schedules were employed. The in-vitro methods produced six successful hybrid lines, but the in-vivo schedules produced none. Resistance to both CPA and MeCCNU was expressed dominantly in the hybrids. The hybrids had chromosome modes ranging from 68 to 78. This study shows that CPA and MeCCNU can be used both as markers and as selective agents, and that CPA and MeCCNU resistance in L1210 leukemia are dominantly expressed in the hybrid.

Alkylating Agents↗
PubMed1986

Temporal interactions in the Lewis lung tumour between cytotoxic drugs and acute or fractionated radiotherapy.

The suggestion was examined, that acute irradiation might be combined with some cytotoxic drugs to produce a supra-additive antitumour effect by timing the second treatment to coincide with the period of repopulation by tumour cells that survived the first treatment. The possible interaction of fractionated irradiation with drugs was also studied. Lewis lung tumours were treated in vivo with acute radiation (20 Gy) and 1-(2-chloroethyl)-3-(4-methyl cyclohexyl)-1-nitrosourea (MeCCNU, 10 mg X kg-1), cyclophosphamide (CY, 120 mg X kg-1) or cis-dichlorodiammine platinum (cis-Pt, 10 mg X kg-1) with time intervals ranging from simultaneous to 9 days in either sequence. Tumour response was measured by regrowth delay and combination responses were evaluated relative to calculated "additivity envelopes". With CY and cis-Pt, tumour volume response was approximately additive, whether the drugs were administered simultaneously, or up to 7 days before or after radiation. However, with simultaneous administration, MeCCNU and radiation were supra-additive in terms of volume response, although only additive using a clonogenic cell survival assay. A transplantation experiment suggested that the supra-additive volume response may be due to retarded growth rate in regrowing tumours. In the fractionation studies, drugs were given either at the beginning or at the end of a regime of 5 daily 6 Gy doses. With CY and MeCCNU the drugs were more effective when given with the first radiation dose, but with cis-Pt either regime was equally effective. There was no evidence that repopulation could be exploited to improve therapeutic effect with any of the combination treatments used in this study.

Animals↗