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PubMed1990

Activation of the anticancer drug CCNU into a free radical intermediate via UV irradiation--an ESR study.

We studied the formation of a free radical induced by UV irradiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in benzene. It was determined a stable nitroxide radical by ESR spectroscopy. We confirmed that sterically hindered cyclic amine 2,2,6,6-tetramethyl-4-piperidone (TMPone) was transformed into a corresponding stable free nitroxyl radical during UV irradiation. When CCNU was present, the rate of free radical formation from TMPone increased considerably.

Benzene↗
PubMed1994

A randomised trial of MACC chemotherapy with or without lonidamine in advanced non-small cell lung cancer. Cuneo Lung Cancer Study Group (CuLCaSG)

Combination chemotherapy with anti-proliferative agents is the usual treatment for patients with advanced non-small cell lung cancer (NSCLC), good performance status and no major clinical contraindications. Lonidamine (LND), a new drug with an innovative mechanism of action, might potentiate anti-cancer activity of conventional cytotoxic drugs, with no increase of specific toxicity. Following a pilot study of feasibility, we now report the results of a randomised trial evaluating MACC chemotherapy, as originally described, versus the same regimen+LND. 151 patients with advanced NSCLC were assigned at random to the two treatment arms. LND 150 mg was given orally three times daily. Treatment was continued until progression of disease, unacceptable toxicity or refusal by the patient (median number of cycles of MACC, three for both arms; median duration of LND administration, 8 weeks in the arm concerned). Actual dose intensities (DI) of MACC and LND were, respectively, 100 and 83% of those intended (median values). There was a negative correlation between duration of chemotherapy and the DI of MACC reached in each patient, but no correlation between the duration of treatment with LND and its DI. DIs of LND and MACC were not correlated with each other. In all, 15 objective responses (one complete and four partial responses in the MACC group, 10 partial responses in patients on MACC+LND) were observed. Median progression-free survivals were 20 weeks (confidence interval, CI 14-22) for the group on LND and 17 weeks (CI 12-17) for the control group (non-significant difference). Median overall survivals were, respectively, 30 weeks (CI 23-40) and 27 weeks (CI 22-34), P = non-significant. Toxicity was as expected by the use of MACC, and similar in both arms, except for more severe anaemia and gastric toxicity in the group on MACC+LND. Other uncommon side-effects, seen only in this latter group, were mild to moderate and reversible and included myalgia, asthenia, testicle pain, headache, visual troubles, incubi and dizziness. Subjective tolerance to the treatment, and perception of physical and psychological well-being were rated similarly by patients of both groups. MACC plus LND is a moderately active regimen in advanced NSCLC, with a foreseeable and reversible toxicity of low-medium grade. Potential enhancements of anti-tumour efficacy of chemotherapy, and possible host survival benefits derived from the use of LND are not substantiated by the results of this trial.

Adult↗
PubMed2005

Supratentorial primitive neuroectodermal tumors (S-PNET) in children: A prospective experience with adjuvant intensive chemotherapy and hyperfractionated accelerated radiotherapy.

PURPOSE: Supratentorial primitive neuroectodermal tumors (S-PNET) are rare and have a grim prognosis, frequently taking an aggressive course with local relapse and metastatic spread. We report the results of a mono-institutional therapeutic trial. METHODS AND MATERIALS: We enrolled 15 consecutive patients to preradiation chemotherapy (CT) consisting of high-dose methotrexate, high-dose etoposide, high-dose cyclophosphamide, and high-dose carboplatin, craniospinal irradiation (CSI) with hyperfractionated accelerated radiotherapy (HART) plus focal boost, maintenance with vincristine/lomustine or consolidation with high-dose thiotepa followed by autologous stem-cell rescue. RESULTS: Median age was 9 years; 7 were male, 8 female. Site of disease was pineal in 3, elsewhere in 12. Six patients were had no evidence of disease after surgery (NED). Of those with evidence of disease after surgery (ED), 2 had central nervous system spread. Of the 9 ED patients, 2 had complete response (CR) and 2 partial response (PR) after CT, 4 stable disease, and 1 progressive disease. Of the 7 ED patients before radiotherapy, 1 had CR, 4 PR, and 2 minor response, thus obtaining a 44% CR + PR after CT and 71% after HART. Because of rapid progression in 2 of the first 5 patients, high-dose thiotepa was systematically adopted after HART in the subsequent 10 patients. Six of 15 patients relapsed (4 locally, 1 locally with dissemination, 1 with dissemination) a mean of 6 months after starting CT, 2 developed second tumors; 5 of 6 relapsers died at a median of 13 months. Three-year progression-free survival, event-free survival, and overall survival were 54%, 34%, and 61%, respectively. CONCLUSION: Hyperfractionated accelerated RT was the main tool in obtaining responses in S-PNET; introducing the myeloablative phase improved the prognosis (3/10 vs. 3/5 relapses), though the outcome remained unsatisfactory despite the adoption of this intensive treatment.

Adolescent↗
PubMed2006

Diagnosis and treatment of a feline oral mast cell tumor.

A cat was diagnosed with an oral mast cell tumor following incisional biopsy. The location of the tumor, possible metastasis, financial restraint and patient disposition severely limited therapeutic options. The patient was treated with six doses of 1-(2-chloroethyl)3-cyclohexyl-1-nitrosurea (CCNU) and methylprednisolone acetate. Complete remission was obtained after the third dosing regimen. This is the first documented case of feline oral mast cell tumor and one of a small group of cats with various cancers to be responsive to CCNU treatment.

Animals↗
PubMed1995

Treating esophageal cancer with a combination of chemotherapy, radiation, and excision.

BACKGROUND: Treatment of esophageal cancer has been primarily palliative. Recent studies have shown that preoperative combination chemo- and radiation therapy increases the effectiveness of surgical excision. PATIENTS AND METHODS: Beginning in 1990, 29 patients in the Spokane area were treated with preoperative chemo- and radiation therapy. They were 23 men and 6 women whose mean age was 66 years. Twenty-five had adenocarcinoma, of whom 3 had Barrett's esophagitis. Four had squamous cell carcinoma. The chemotherapy included fluorouracil, cisplatin, and vinblastine. Radiation was given concomitantly, BID for 21 days. Surgical excision was performed about 3 weeks after the last radiation session, pending recovery from cytopenia. RESULTS: There was 1 operative death, for an operative mortality of 3.4%. Twenty-three patients (79%) were found to have no residual cancer at the time of resection. Of this group, 8 died of metastatic cancer at a mean of 15 months postoperatively (range 1 to 28), and 15 were alive at a mean of 28 months (range 12 to 46). Six patients (21%) had residual cancer in the resected specimen, either at the primary site or--more often--in adjacent lymph nodes. Five have died at 6, 8, 9, 24, and 28 months postoperatively; 1 remains alive at 14 months. The mean survival among these 6 patients is 15 months. CONCLUSIONS: Combined chemo- and radiation therapy prior to esophagectomy appeared to improve outcome in this small series of patients with esophageal cancer. Local control was excellent, but distant metastasis continues to be a significant problem.

Adenocarcinoma↗
PubMed1986

Five-year survival in treated stage I and II small cell carcinoma of the lung.

Ten consecutive patients were treated more than five years ago, for small cell carcinoma of the lung in clinical and surgical stages I or II. Patients underwent initial surgical resection, followed by intensive combination chemotherapy for at least a year, or to limit of tolerance. Four patients were classified as stage II, T2 N1; 4 had T2 N0; and 2 had T1 N0. One patient (T2 N1) died of tumor recurrence in the central nervous system 14 months after resection. Two died of other causes before five years, one (T2 N0) of a pulmonary embolus on the seventh postoperative day, and the other (T2 N1) of carcinoma of the prostate at 50 months. Seven patients (70%) remained well and disease-free at five years postoperation. Two of the 7 died of unrelated causes, one (T2 N0) at 72 months and one (T2 N1) at 108 months. Five remain well at 61 to 112 months after resection. Although this series is small, no reports have shown comparable survival in a defined group of small cell carcinoma patients treated nonoperatively or by surgical resection alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Release of 7-alkylguanines from haloethylnitrosourea-treated DNA by E. coli 3-methyladenine-DNA glycosylase II.

Previous studies have related DNA modification by the haloethylnitrosoureas to their antitumor activity. Repair of this damage, particularly by O6-alkylguanine-DNA alkyltransferase, has been linked to tumor resistance by several previous investigations. We report here that E. coli 3-methyladenine-DNA glycosylase II can also remove several of the DNA modifications caused by the haloethylnitrosoureas. 7-Chloroethylguanine, 7-hydroxyethylguanine, and diguan-7-ylethane are all released into the supernatant from DNA modified by N-[2-chloroethyl-1,2-14C]-N'-cyclohexyl-N-nitrosourea. Release of diguan-7-ylethane is of particular interest since this entity evidently represents a DNA intrastrand cross-link. If a similar activity is present in mammalian cells, it might be an important source of resistance to the therapeutic action of the haloethylnitrosoureas.

Chromatography, High Pressure Liquid↗
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↗
PubMed1975

CCNU in brain tumours.

CCNU, a nitrosourea compound, has been found effective in the management of both primary and secondary tumours of the brain. It is proposed to carry out an investigation comparing radiotherapy alone with radiotherapy and CCNU combined, in cerebral gliomata.

Adolescent↗
PubMed1984

Management of malignant melanoma: a retrospective analysis of 182 patients.

The records of 182 patients, referred to the Regional Radiotherapy Centre, Newcastle upon Tyne between January 1975 and December 1980, have been reviewed to evaluate the results of different modes of treatment. Fifty-two patients were managed for Stage 1, 83 for Stage 2 and 47 for Stage 3 disease. Fifty-seven patients with 95 sites of disease were given chemotherapy. The overall response rate was 35% (complete response (CR) 14%, partial response (PR) 21%) (median duration of remission = 4 months). Sixty-three patients with 74 sites of disease were treated by radiotherapy. The overall response rate was 73% (CR 47%, PR 26%) (median duration of remission = 7 months). In Stage 2 disease, no significant difference in the disease-free or overall survival was found between four different treatment groups. In disseminated disease, chemotherapy had little impact on the survival of patients with visceral metastases, while those with skin and lymph node metastases had significantly better survival. Radiotherapy was tolerated better and had lower morbidity than chemotherapy. The role of both modes in the management of advanced disease is discussed.

Adolescent↗
PubMed1991

Thyroid function after treatment of brain tumors in children.

In 134 children who had been treated for a brain tumor not involving the hypothalamic-pituitary axis, thyroid function was assessed up to 24 years after treatment with cranial or craniospinal irradiation. In addition, 78 children received up to 2 years of cytotoxic chemotherapy. Of 85 children who received craniospinal irradiation, 30 (35%) had abnormalities of thyroid function, and 10 (20%) of 49 who received cranial irradiation had such abnormalities. Frank hypothyroidism developed in three children and thyrotoxicosis in one. Thirty-six children had an elevated thyroid-stimulating hormone level in the presence of a normal thyroxine level; in 16 of them the thyroid-stimulating hormone level subsequently returned to normal. Twenty-eight children who were treated between 1960 and 1970 were excluded from the analysis. Of 34 children who received cranial irradiation, five had thyroid dysfunction and 24 of 72 who received craniospinal irradiation had such dysfunction (p = 0.013). Thyroid dysfunction was present in 4 of 35 children who received no chemotherapy and in 25 of 71 who received chemotherapy (p = 0.014). Direct irradiation plus chemotherapy was more damaging than irradiation alone. These data confirm the high incidence of thyroid dysfunction when the thyroid gland is included in the radiation field. However, in a high proportion, the thyroid abnormalities are minor and revert to normal with time; life-long replacement therapy with thyroxine may be unnecessary.

Adolescent↗
PubMed1982

Cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy versus chloroethyl-cyclohexy-nitrosourea in the treatment of metastatic prostatic cancer.

In a prospective, randomized study the effect of cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy was compared to the single agent, chloroethyl-cyclohexy-nitrosourea, in the treatment of hormonally refractive metastatic prostatic carcinoma. All patients could be evaluated and were followed for at least 2 years or until death. Responses were defined by the National Prostatic Cancer Project criteria. Of 20 patients who received cyclophosphamide, methotrexate and 5-fluorouracil 3 (15 per cent) had partial (median duration of 2.5 months), 4 (20 per cent) had stable (median duration of 5 months) and 13 had progression of the disease. Of 20 patients who received chloroethyl-cyclohexy-nitrosourea none had a partial response, 6 (30 per cent) had stability (median duration of 6.2 months) and 13 had progression of the disease. The over-all response rate for patients receiving cyclophosphamide, methotrexate and 5-fluorouracil was 35 per cent (stable plus partial regressions) and it was 30 per cent for those receiving chloroethyl-cyclohexy-nitrosourea (stable only). Subjective improvement was noted in all 7 patients who responded to combination chemotherapy and in 3 of the 6 patients who responded to the single agent. After 2 courses resistant patients were crossed over to the opposite regimen and none had an objective, stable or subjective response. Although the duration of response was short (2 to 6 months) patients with partial regressions or stabilized disease survived longer (p less than 0.05) than patients whose disease progressed (52 versus 24 weeks, respectively). The mean interval from diagnosis to chemotherapy (lead time) was 40 months for patients who responded to chemotherapy compared to 19 months for those with progression, which suggested a slower growing pattern of disease in those who did respond. There was no improvement in cohort survival with either treatment regimen. Over-all response rates to cyclophosphamide, methotrexate and 5-fluorouracil were not superior to reported responses to cyclophosphamide alone, and both treatment regimens appeared to be only marginally effective in the treatment of endocrine-resistant, advanced prostatic cancer.

Aged↗
PubMed1979

Chemotherapy of advanced transitional cell carcinoma of the renal pelvis: report of 3 cases treated with vinblastine and chloroethyl-cyclohexyl-nitrosourea.

Three patients with advanced transitional cell carcinoma of the renal pelvis were treated with 5 mg./m.2 body surface vinblastine intravenously weekly and 130 mg./m.2 chloroethyl-cyclohexyl-nitrosourea orally with 6-week intervals. One patient had a partial remission for 1.5 months and 2 had stationary disease for 6 and 2 months.

Carcinoma, Transitional Cell↗
PubMed1992

Metastatic bronchioloalveolar carcinoma and metastatic adenocarcinoma of the lung: comparison of clinical manifestations, chemotherapeutic responses, and prognosis.

Between 1975 and 1985, 25 patients with metastatic bronchioloalveolar carcinoma and 223 patients with metastatic adenocarcinoma of the lung received experimental cisplatin-based chemotherapy at the Mayo Clinic. The chemotherapeutic response rates were 32% and 33%, respectively. The median times to progression of disease were identical (3 months in both groups). The median survival times were 4 months and 6 months, respectively. Metastatic bronchioloalveolar carcinoma is an aggressive disease that is associated with a poor prognosis, similar to metastatic adenocarcinoma of the lung.

Adenocarcinoma↗
PubMed1997

Induction of specific-locus and dominant lethal mutations in male mice by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU).

1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) induced dominant lethal and specific-locus mutations in male mice. For both compounds the germ cell stage sensitive to the induction of dominant lethal mutations was dose dependent. A dose of 5 mg BCNU per kg b.wt. induced dominant lethal mutations primarily in spermatocytes, whereas higher doses of BCNU induced dominant lethals in spermatids and spermatocytes. Following doses of 5 and 10 mg CCNU per kg b.wt. dominant lethals were induced in spermatids and spermatocytes similar to the results for higher doses of BCNU. Higher dose exposure to BCNU and CCNU was associated with dominant lethals expressed as pre-implantation loss (reduction in total number of implants). In addition, higher doses of CCNU showed a cytotoxic effect in differentiating spermatogonia. Both compounds induced specific-locus mutations in post-spermatogonial germ cell stages of mice. However, CCNU increased also the specific-locus mutation frequency in spermatogonia in two out of three experiments. We conclude in analogy with criteria developed by IARC, that BCNU and CCNU are potential human mutagens.

Animals↗