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PubMed1979

Chemotherapy of gastric and pancreatic carcinoma: a controlled evaluation of combinations of 5-fluorouracil with nitrosoureas and "lactones".

By random assignment a total of 176 eligible patients with advanced nonmeasurable pancreatic carcinoma were treated with 5-fluorouracil (5-FU) either alone or in combination with a nitrosourea (streptozotocin), in combination with a "lactone" (spironolactone), or in combination with both. By random assignment a total of 179 patients with advanced nonmeasurable gastric carcinoma were treated with 5-FU either alone or in combination with a nitrosourea (methyl CCNU), in combination with a lactone (testolactone), or in combination with both. The median survival period for all pancreatic carcinoma patients was 17 weeks, and for all gastric carcinoma patients 30 weeks. The addition of the nitrosoureas or the lactones or a combination of both produced no improvement in length of patient survival for either primary carcinoma when compared to treatment with 5-FU alone.

Adenocarcinoma↗
PubMed2005

Beneficial effects of spin-labelled nitrosourea on CCNU-induced oxidative stress in rat blood compared with vitamin E.

This study was carried out to determine the effects of a recently synthesized 1-ethyl-3-[4-(2,2,6,6-tetra-methylpiperidine-1-oxyl)]-1-nitrosourea (SLENU), compared with vitamin E as a positive control, on 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced oxidative stress in rats. We determined plasma malonyl dialdehyde (MDA) levels and the activities of erythrocyte superoxide dismutase (SOD) and catalase (CAT). Forty two white albino healthy rats were treated once daily for 30 days with oral preparations of CCNU (12.5 mg/kg and 25 mg/kg), SLENU (25-200 mg/kg), and combinations of these. The CCNU-induced increase in plasma MDA level and the usual decrease in erythrocyte SOD and CAT activities were reversed by SLENU, but not by vitamin E. We have previously demonstrated that SLENU is a superoxide scavenger. A combination of our present findings with previous results thus leads us to proposing a new chemotherapeutic combination of CCNU and SLENU that is devoid of high toxicity.

Animals↗
PubMed2005

Antitumor activity of Nitronaphthal-NU, a novel mixed-function agent.

Nitronaphthal-NU (Compound 1) was synthesized as a mixed-function antitumor agent based on the structures of the clinical drug CCNU and experimental compound Mitonafide. In vitro screening in four human tumor cell lines namely SNB-78 CNS, HOP-62 Lung, T47D Breast and SiHa - cervix revealed significant cytotoxicity in the former two cell lines much greater than CCNU and comparable to Mitonafide used as standards. In vivo antitumoral potency assessed in the murine ascites tumors Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times of drug treated (T) over untreated control (C) mice, revealed highly significant (p<0.001) tumor regression effects greater than standards. Life span of mice bearing advanced tumor for 10 days before the drug challenge was also considerably increased. Its toxicity was assessed in vivo in normal and S-180 bearing mice by measuring drug-induced changes in haematological parameters, femoral bone marrow and splenic cellularities as well as hepatotoxicity and nephrotoxicity sequentially on days 9, 15 and 21 following drug treatment at the optimum dose of 50 mg/kg from day 1 to 7. Results indicate that it did not adversely affect haematopoiesis. The other parameters were within normal limit. The compound comparable to standards inhibited the synthesis of DNA and RNA in S-1 80 tumor cells.

Alkylation↗
PubMed1991

Effect of O6-benzylguanine analogues on sensitivity of human tumor cells to the cytotoxic effects of alkylating agents.

The effect of O6-benzylguanine, O6-(p-chlorobenzyl)guanine, and O6-(p-methylbenzyl)guanine on the sensitivity of various human tumor cell lines to alkylating agents is evaluated. The sensitivity of human colon tumor cells, HT29, to the chloroethylating agents, 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 2-chloroethyl(methylsulfonyl) methanesulfonate (clomesone), and chlorozotocin was increased by pretreatment for 2 h with 25 microM of each analogue. O6-Benzylguanine was slightly more effective as a sensitizer in HT29 cells than the p-chlorobenzyl and p-methylbenzyl analogues. However, all analogues sensitized SF767 glioma cells to the cytotoxic effects of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and clomesone to the same degree. Both cell lines were sensitized to the methylating agents streptozotocin and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide, the active intermediate of 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide, by pretreatment with 10 microM O6-benzylguanine for 2 h. The number of Raji cells surviving 50 microM clomesone decreased 3-fold upon pretreatment for 2 h with 1 microM O6-benzylguanine. The degree of enhancement was dependent on the amount of alkyltransferase protein present in cell lines. For example, HT29 cells (alkyltransferase activity, 381 fmol/mg protein) exhibited a greater degree of enhancement when treated with O6-benzylguanine than SF767 (77 fmol/mg protein) and M19-MEL melanoma (36 fmol/mg protein) cells. There was no enhancement observed in mer- cell lines, U251 (less than 2 fmol/mg protein), and BE (3 fmol/mg protein), or with alkylating agents which did not produce a cytotoxic lesion at the O6 position of guanine in DNA such as cisplatin or 4-hydroperoxycyclophosphamide. Our studies suggest that O6-benzylguanine analogues may have utility in mer+ tumors as an adjuvant to a variety of alkylating agents which produce a toxic lesion at the O6 position of guanine.

Alkylating Agents↗
PubMedDate not supplied

Radiation treatment plus CCNU plus the radiosensitizer lonidamine in malignant gliomas operated.

From June 1988 to January 1990, 28 patients with primary brain tumours were operated and treated with radiotherapy (RT) (50 Gy whole brain + 10 Gy boost to tumour bed) + cyclohexylnitrosourea (CCNU) 130 mg/msq p.o. every 6 weeks + the radiosensitizer Lonidamine (LND) (150 mg T.I.D. for the whole duration of treatment). Myelotoxicity of this regimen was acceptable, with two cases of grade IV leukopenia and thrombocytopenia requiring discontinuation of treatment. LND was discontinued in 6 patients for major toxicity (myalgias and/or testicular pain), and 3 additional patients required dose reduction of this drug. The median follow-up time of the patients on study was 12 months. The median survival time (MST) was 5 months for grade IV astrocytomas (n = 8) and 16 months for grade III lesions (= 20). No correlation was seen between survival of patients and DNA content, measured by flow cytometry, or levels of O6- alkylguanine-DNA alkyltransferase, an enzyme that repairs the CCNU-induced DNA damage.

Brain Neoplasms↗
PubMed1991

[Alternating chemotherapeutic treatment in patients with localized undifferentiated small-cell carcinoma of the lung].

The results obtained from 23 patients suffering small cell lung carcinoma limited to the thorax, treated with 4 cycles of cyclophosphamide, adriamycin, vincristine alternating with cisplatin and VP/16, followed by mediastinal and holocranial prophylactic radiotherapy in patients with a complete response (CR) are here presented. An 87% of global responses were obtained with a 64% rate of RC. The average survival rate was 12 months with an 18% of patients alive two years after treatment. The main toxicity was hematologic and neurologic. Even if this alternating regime produces a high response rate, the results are not superior to those obtained with conventional chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Salvage chemotherapy with CCNU and methotrexate for small cell lung cancer resistant to CAV/PE alternating chemotherapy.

CCNU and methotrexate were employed as salvage treatment in 34 small cell lung cancer patients resistant to CAV/PE alternating induction chemotherapy. In the 33 evaluable patients we observed an objective response rate of 21.2% and 3% complete response; median survival was 4 months with 2 patients alive 18 months from starting salvages chemotherapy. The treatment was well tolerated. CCNU and methotrexate has shown to be a moderately active and tolerable salvage treatment for small cell lung cancer after CAV/PE alternating first-line chemotherapy.

Adult↗
PubMedDate not supplied

Hospital in the home (HITH) care following autologous stem cell transplantation for lymphoma and multiple myeloma.

BACKGROUND: Advances in outpatient and supportive care and increased pressure on hospital bed usage has led to the investigation of hospital in the home (HITH) management following autologous haematologous stem cell transplantation (AutoHSCT) for patients with multiple myeloma or lymphoma. DESIGN: The Newcastle Mater Hospital Haematology Unit together with the Mater Acute Care Community Service (MACCS) developed a protocol for HITH care following AutoHSCT. OUTCOMES: Clinical outcomes of the protocol were audited: 40% (13) of patients were suitable candidates for HITH care post transplantation. Of these 84.6% (11) were readmitted to the haematology unit within seven days of discharge from hospital. CONCLUSION: Our preliminary experience suggests that with adequate infrastructure support and rigorous patient selection this model of care is both safe and feasible.

Adult↗
PubMed1990

Induction of chromosome breaks and sister chromatid exchanges in patients with Hodgkin's disease by two combination chemotherapy regimens of different leukemogenic potential.

The success of various combination chemotherapies in the treatment of cancer is compromised by their potential to cause secondary leukemia. Previous studies have suggested that the alkylating agents used in some regimens are the major etiological factor in these leukemias. In this study, we compared the abilities of two standard regimens used in the treatment of Hodgkin's disease to cause chromosome breaks and sister chromatid exchanges, the two most common types of chromosomal damage induced by alkylating agents. These regimens are MOPP [mechlorethamine-vincristine (Oncovin)-procarbazine-prednisone] and CVPP-ABDIC [cyclophosphamide-vinblastine-procarbazine-prednisone-doxorubicin (Adriamycin)-bleomycin-dacarbazine-1-(2-chloroethyl)-3-cyclohexyl-1- nitrosourea]. Our study demonstrated that (a) levels of spontaneous chromosome breaks and sister chromatid exchanges were low in untreated Hodgkin's disease patients; (b) significantly higher levels of these damages were induced in patients receiving eight cycles of CVPP-ABDIC, as compared with their pretreatment levels; (c) significantly elevated levels of sister chromatid exchanges, but not chromosome breaks, were induced in patients receiving two cycles of MOPP; and (d) no differences in the effect of these two regimens on cell cycle kinetics were observed. Although MOPP therapy has been reported to have higher rates of secondary leukemia than CVPP-ABDIC, our studies show that eight cycles of CVPP-ABDIC are more potent than two cycles of MOPP in inducing chromosome damage in patients during treatments.

Adult↗
PubMedDate not supplied

Etoposide (VP-16) containing combination chemotherapy for treatment of patients with small cell lung cancer.

A combination chemotherapy consisting of VP-16, vincristine, cyclophosphamide and CCNU was used to treat 24 patients of small cell lung cancer (extensive stage disease - 15 and limited stage - 9). In addition, radiotherapy of 1000 to 4000 cGys was given to primary disease in chest in 16 patients. The overall response rate was 95.8% with complete response (CR) in 9 (37.5%) and partial (PR) in 14 (58.3%) cases. The overall median survival was 24 weeks. In patients with CR, it was 39 weeks and in those with PR this was 22.5 weeks. The lone non-responder survived for only 8 weeks. The drugs were well tolerated.

Adult↗
PubMed1990

Pulmonary effects of cytotoxic agents other than bleomycin.

Multiple chemotherapeutic agents have been reported to cause pulmonary injury, usually manifested as interstitial pneumonitis and fibrosis. Several unique presentations have been described for mitomycin, methotrexate, and the combinations of mitomycin and vinca alkaloids. Mechanisms of lung injury remain mostly speculative, although ongoing investigations may someday elucidate such pathways of injury. With a greater understanding of how these agents damage lung tissue, physicians may be able to more safely administer these drugs to patients. The drugs which have been shown to cause pulmonary injury most frequently are BCNU, mitomycin (with and without vinca alkaloids), and methotrexate. All physicians using cytotoxic drugs must be aware of the potential for lung injury with these agents.

Antineoplastic Agents↗
PubMed2006

Gliomatosis cerebri treatment in 11 elderly patients.

The Authors report their experience in the treatment of eleven patients over 70 years old (range from 70 to 83, average age 74.8, 7 males and 4 females), with histologically proven diagnosis of glioblastoma multiforme. The GC golden standard treatment is still debated, particularly in elderly patients. All the patients underwent a first line treament with chemotherapy (Temozolomide), followed by Whole Brain Radiotherapy (WBRT) and PCV schedule without Vincristine in case of progression of the disease. The median survival was 16.3 months, ranging from 13 to 22 months. According to our experience, elderly patients should undergo the same treatment of younger patients, provided they are in good health conditions.

Aged↗
PubMed1990

[Results of a randomized polychemotherapy study in malignant melanoma].

A polychemotherapy (DTIC, vincristine, ftorafur, hydroxycarbamide) devised with reference to the results of short-term sensitivity tests in cell culture is compared with single-agent chemotherapy with DTIC in malignant melanoma. Effectiveness was investigated in a randomized prospective study in cases of high-risk melanoma in clinical stage I, in clinical stage II after lymphadenectomy and in clinical stage III after tumour debulking. The results recorded allow no positive effects of either form of chemotherapy in stage I disease compared with surgical treatment only in a control group. In contrast, a statistically significant advantage of the polychemotherapy was noted in stage II compared with a control group. There was no significant difference in the results of treatment between the two forms of chemotherapy in stage III. No complete remissions of long duration have been achieved.

Adolescent↗
PubMed1991

New approaches to the chemotherapy of melanoma.

Several new investigational agents have shown some promise in the treatment of patients with disseminated melanoma. While earlier studies of combination chemotherapy led to increased toxicity without improved anti-tumor effect, more recent combination regimens have produced responses up to 50%. One of these is a dose-intensification regimen using high-dose cisplatin and the chemoprotective drug WR-2721. Other treatments under study include autologous bone marrow transplantation plus thiotepa, a combination regimen of chemotherapy and interferon, and newer agents such as taxol, tauromustine, and detrorubicin.

Alkaloids↗
PubMed1992

Effect of O6-benzylguanine on the sensitivity of human tumor xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea and on DNA interstrand cross-link formation.

We have previously shown that O6-benzylguanine can be used to deplete cells of the DNA repair protein O6-alkylguanine-DNA alkyltransferase and to enhance the sensitivity of human glioma (SF767) and colon tumor (HT29) cells to the cytotoxic effects of alkylnitrosoureas. In the present study, the combination of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was evaluated in vitro to determine the number of DNA interstrand cross-links formed and in vivo to compare the therapeutic index with that of BCNU alone. The number of DNA interstrand cross-links, as measured by alkaline elution, was increased in HT29 cells treated with 10 microM O6-benzylguanine for 2 h prior to BCNU exposure compared to cells treated with BCNU only. The number of single strand breaks was not increased by prior exposure to O6-benzylguanine. To evaluate the therapeutic index, HT29 and SF767 cells were grown as xenografts in nude mice and the tumor growth rate after treatment with BCNU alone was compared with the rate after treatment with O6-benzylguanine and BCNU. Treatment was administered i.p. when tumors reached 100-200 mm3. For animals bearing HT29 xenografts that were treated with 60 mg/kg O6-benzylguanine 1 h prior to 20 mg/kg BCNU, the average time for tumor volume to increase by 200% was 25 days, compared to 10 days for animals treated with 20 mg/kg BCNU alone. For animals bearing SF767 xenografts, the tumor growth of controls was not significantly different from that of animals treated with O6-benzylguanine alone or BCNU alone up to the maximally tolerated dose (50 mg/kg). For these 3 groups, the average time for tumors to reach 300 mm3 was 9-12 days. However, when animals were treated with 80 mg/kg O6-benzylguanine 1 h prior to receiving 20 mg/kg BCNU tumor size did not increase for at least 21 days. Our studies demonstrate that the therapeutic index of BCNU can be increased when given in combination with O6-benzylguanine.

Animals↗