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The therapeutic potential of misonidazole enhancement of alkylating agent cytotoxicity.

The effect of prolonged exposure to low misonidazole (MISO) levels on the cytotoxicity of three alkylating agents was studied in mouse tumors. A concentration of 100 micrograms/ml was maintained in the plasma for 7 hr by multiple injections of MISO. Cyclophosphamide (CYC). Melphalan (L-PAM), or CCNU were given after 4 hrs of MISO exposure. In each case, prolonged low level MISO exposure enhanced tumor response as measured by regrowth delay or a cloning assay. The effect of this treatment was also studied in several normal tissues: bone marrow, white blood cell counts, and spermatogonia. In none of these was any enhancement seen after prolonged MISO exposure. These encouraging results show that clinically relevant exposures to MISO can greatly improve tumor response to alkylating agents without increased normal tissue toxicity.

Alkylating Agents↗
PubMed1983

Combined modality treatment of regional small cell undifferentiated carcinoma of the lung: a cooperative study of the RTOG and ECOG.

Between 1975 and 1979, 271 patients with regional small cell undifferentiated (including oat cell) carcinoma of the lung were entered into a study involving treatment by radiation therapy (4500 cGy (rad) in five weeks) to the primary tumor, mediastinum and supraclavicular lymph nodes, and a randomization to receive or not receive prophylactic treatment of the brain (3000 cGy in two weeks) and a randomization to prophylactic or delayed chemotherapy (cyclophosphamide and CCNU). Analysis of the data indicates that the median survival for responders (53 weeks) was significantly longer than that of the non-responders and partial responders (37 and 34 weeks). Median survival by treatment arm was 48 weeks for thoracic irradiation (TI), brain irradiation (BI), and early chemotherapy (CT), 44 weeks for TI alone, 41 weeks for TI and CT, 38 weeks for TI and BI. Regional complete and partial tumor responses were 52 and 25% for prophylactic chemotherapy and 44 and 35% for delayed chemotherapy. The site of first failure was regional in 12%, regional and distant simultaneously in 21%, and distant only in 46%. Elective brain irradiation significantly reduced the incidence of brain metastases from 21 and 5%, but did not improve survival.

Brain Neoplasms↗
PubMed1983

Liver complications in lymphomas treated with a combination of chemotherapy and radiotherapy: preliminary results.

From May 1978 to May 1981, a total of 20 patients (18 patients with Non Hodgkin Lymphomas + 2 patients with Stage IV Hodgkin's disease) were treated with chemotherapy and whole or upper abdominal radiotherapy. All the patients were in complete remission at the time of irradiation. Shielding of the kidneys was effected at the start of treatment and the right lobe of the liver was shielded after a dose of 20 Gy was delivered. As of January 1982, 17 of the patients were alive and free of disease with a follow-up ranging from 6 to 32 months (mean follow-up of 18.5 months). Two patients were dead from their disease. Alterations in liver chemistry were observed in 5 patients, clinical jaundice or transient hepatomegaly along with changes in liver chemistry in 4 patients, classical veno-occlusive disease in 2 patients and 7 of the patients did not develop any complication. No death from complications were observed. The contribution of the following factors such as radiotherapy dose to the liver, drugs, nutritional status and associated medical conditions, towards the development of complications have been analyzed in detail.

Adult↗
PubMed1983

Hemibody radiation, an active therapeutic modality for the management of patients with small cell lung cancer.

In a previously published paper, the results of a preliminary clinical trial comparing systemic radiation (upper and lower hemibody technique) versus systemic chemotherapy in the management of all stages of small cell lung cancer (SCLC), suggested that hemibody radiation (HBI) was as efficient as systemic chemotherapy, particularly for patients with early disease. We are now presenting the final results of the above trial. The two year survival has shown that as many patients in the HBI as in the chemotherapy arm have reached this endpoint. However, there is a difference in favor of chemotherapy on both the median and one year survival for those patients with advanced stages. Therefore, as of June 1981, we have initiated a study incorporating HBI as a consolidating-maintenance agent for patients with all stages of the disease who have received a 3 1/2 months induction systemic chemotherapy plus local chest irradiation. Up to date, 65 patients have been entered and our median survival for those who received the complete treatment is 62.5 weeks.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Pilot studies of superfractionated radiotherapy and combination chemotherapy in limited oat cell carcinoma of the bronchus.

There are sound radiobiologic and suggestive clinical rationale for superfractionating the radiotherapeutic regimens employed for the therapy of rapidly growing malignancies. Oat cell carcinoma of the bronchus is such a tumor. We report our experience combining aggressive systemic combination chemotherapy with superfractionated radiotherapy for the treatment of "limited" oat cell carcinoma of the bronchus. Overall, patient tolerance was satisfactory and a complete remission rate of 74% was achieved. It remains to be proven, in a prospective randomized fashion, whether this approach is superior to current conventional management.

Adult↗
PubMed1984

Modification of chemotherapy by nitroimidazoles.

The potentiation of chemotherapeutic agents by radiation sensitizers has been extensively studied for several years. There is little doubt that the effectiveness of certain anti-cancer drugs, primarily alkylating agents, can readily be enhanced both in vitro and in vivo through the addition of a sensitizer. While enhanced effects have been observed in certain critical normal tissues, in general most animal model studies have demonstrated a therapeutic gain at large sensitizer doses. This approach to combination therapies therefore appears promising. Yet many questions concerning the interaction between chemotherapeutic agents and radiosensitizers, particularly in the area of mechanisms of action, still remain. This overview attempts to focus on some of these questions. Four aspects of modification of chemotherapy by nitroimidazoles are reviewed and discussed. These address the importance in chemopotentiation of i) hypoxia, ii) alterations in DNA damage and/or repair, iii) depletion of intracellular sulfhydryls and iv) modification of drug pharmacokinetics. It is concluded that: i) even though chemopotentiation can occur at intermediate oxygen levels, hypoxia ultimately plays a pivotal role, ii) no single unifying mechanism for chemopotentiation exists; alterations in drug pharmacokinetics, cellular SH levels and DNA damage/repair all are involved, the relative importance of each factor is dependent on the particular drug-sensitizer combination, iii) it is important to continue the evaluation of chemopotentiation under conditions mimicking clinically achievable sensitizer pharmacokinetics and iv) further investigations into more effective utilization of chemopotentiation are warranted.

Animals↗
PubMed1984

Preliminary evaluation of isocyanate-generating nitroheterocycles as chemosensitizers, radiosensitizers and hypoxic cell cytotoxic agents.

Nitro-compounds containing an acetylated acetohydroxamic acid side chain in the N-1 position of a 5-membered ring nitrogen heterocycle have been synthesized. These compounds, which can generate isocyanates via a Lossen rearrangement, were evaluated in order to test the hypothesis that they may be effective radiation and chemosensitizing agents by nature of their isocyanate-associated carbamoylating potential. Evaluation of one such compound, DJW-77 (1(O-Acetyl-Acetohydroxamic acid)-3-nitropyrazole) as a radiation sensitizer, chemosensitizer and hypoxic cell toxin is reported. In vitro DJW-77 demonstrates a potent selective cytotoxicity toward hypoxic EMT-6 tumor cells, is an effective potentiator of CCNU toxicity and is comparable to MISO with respect to its radiation-sensitizing potential. The activity of the drug is eliminated under aerobic conditions. To test the hypothesis that the activity of DJW-77 is related to isocyanate generation, the non-acetylated analog of DJW-77 (which does not directly undergo the Lossen rearrangement) and the parent 3-nitropyrazole ring structure were evaluated. Neither compound enhanced CCNU toxicity, and on an equimolar basis were inferior to DJW-77 as radiation sensitizers. While the non-acetylated analog was cytotoxic to hypoxic cells, relative to DJW-77 this activity was substantially reduced. These studies indicate that the addition of a side chain capable of generating an isocyanate can enhance the cytotoxicity and sensitizing activity of nitroheterocycles.

Animals↗
PubMed1984

Survival in subpopulations of cells derived from solid KHT sarcomas by centrifugal elutriation following treatment with CCNU and MISO.

Misonidazole (MISO) has been shown to enhance the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in a number of different animal tumor systems. We have investigated the response to therapy of the various subpopulations of cells comprising the KHT sarcoma, to determine whether chemopotentiation occurred as a preferential enhancement of killing in one subpopulation of cells. Twenty-four hr after drug treatment, cells dissociated from solid tumors were separated into homogeneous populations based on cell size by the technique of centrifugal elutriation. By this method the majority of the non-neoplastic cells could be removed and the tumor cells separated into fractions containing 90 to 95% G1 cells, 70 to 75% S cells and 70 to 80% G2M cells. Clonogenic cell survival was measured for each elutriated fraction. In vivo treatment with 0.5 mg/g MISO produced no measurable cell-kill across the cell cycle. Those cells in late G1 and S phase 24 hr after treatment were most sensitive to CCNU alone. The enhancement of CCNU cytotoxicity by MISO occurred primarily in the early G1 and S fractions. These data suggest that chemopotentiation does not occur equally in all tumor cell subpopulations and that some specificity of enhanced cell killing exists.

Animals↗
PubMed1984

The effect in the KHT sarcoma of CCNU and MISO on cell cycle progression evaluated by flow-cytometry.

Previous studies using the KHT sarcoma have shown that misonidazole (MISO) enhances the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) by as much as a factor of 2.0. In the present study flow cytometry was used to monitor the changing DNA distributions of cells dissociated from solid tumors at successive times following treatment with CCNU, applied either alone or in combination with 0.5 mg/g MISO. The proportion of cells in late S and the G2M phases of the cell cycle increased gradually after CCNU treatment. MISO did not significantly change this block in cell progression, which persisted for at least 48 hr after treatment in all cases. CCNU shows marked carbamoylating activity, which has been associated with inhibition of RNA processing and with the degree of chemopotentiation achieved with MISO. Consequently, to evaluate whether MISO chemopotentiation was influencing the RNA distributions in tumors, RNA histograms were generated using acridine orange to differentially stain cellular DNA and RNA. By 24 hr after treatment, CCNU clearly altered the distribution of RNA, but no significant differences could be detected between results obtained from drug and drug plus sensitizer treated groups. These studies demonstrate the effect of CCNU on cell cycle progression in vivo. The addition of MISO did not result in further perturbation of the total tumor population, suggesting that cell cycle redistribution does not play a major role in chemopotentiation by MISO.

Animals↗
PubMed1984

Enhanced tumor responses through therapies combining CCNU, MISO and radiation.

Studies were performed to determine whether the radiation sensitizer misonidazole (MISO) could enhance the tumor control probability in a treatment strategy combining radiation and the nitrosourea 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). In initial experiments KHT sarcoma-bearing mice were injected with 1.0 mg/g of MISO simultaneously with a 20 mg/kg dose of CCNU 30-40 min prior to irradiation (1500 rad). These timings were chosen to maximize the effectiveness of MISO both as a chemopotentiator and radiosensitizer. With this treatment protocol approximately 60% of the mice were found to be tumor-free 100 days post treatment. By comparison all 2 agent combinations led to 0% cures. To evaluate the relative importance of chemopotentiation versus radiosensitization in the 3 agent protocol, tumors were treated with MISO plus one anti-tumor agent (either radiation of CCNU) and then at times ranging from 0 to 24 hr later exposed to the other agent. When the time between treatments was 0 to 6 hr, a 60 to 80% tumor control rate was achieved for both MISO plus radiation followed by CCNU and MISO plus CCNU followed by radiation. However if the time interval was increased to 18 or 24 hr, the cure rate in the former treatment regimen dropped to 10% while that of the latter remained high at 40%. These results were not due to the radiation-CCNU sequence but rather reflected the ability of the sensitizer to act as a chemopotentiator when CCNU is given 0 to 6 hr after the MISO-radiation combination. This was not the case when the MISO-radiation combination was administered 18 or 24 hr prior to CCNU. The data therefore indicate that 1) improved tumor responses may be achieved when MISO is added to a radiation-chemotherapy combination and 2) MISO may be more effective in such a protocol when utilized as a chemopotentiator.

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↗
PubMed1984

Modification of alkylating agent cytotoxicity by cisplatin.

The effect of cisplatin on the cytotoxicity of alkylating agents in the RIF-1 tumor both in vivo and in vitro was investigated. A single dose of cisplatin (1 mg/kg) enhanced the in vivo tumor killing by melphalan (L-PAM; 8 mg/kg). The effect was maximal when cisplatin was given between 3 hours before and 1 hour after injecting L-PAM; the enhancement was lost as the time interval increased. Similar results were obtained with cyclophosphamide (CYT; 75 mg/kg) and CCNU (50 mg/kg) although the enhancement was much less than that seen with L-PAM. The enhancement by cisplatin was constant at all L-PAM doses as measured by both cloning assay and regrowth delay. Measurements of white blood cell counts four days after drug administration suggests that a therapeutic gain can be achieved. Exponential and plateau phase RIF-1 cells grown in monolayer culture were also exposed to various L-PAM doses. A 1 hour pre-exposure to cisplatin (0.5 micrograms/ml) under aerobic conditions increased the cell killing by L-PAM. The results are discussed with reference to the possible reasons for the therapeutic gain.

Alkylating Agents↗
PubMed1984

A phase I study of the combination of benznidazole and CCNU in man.

The 2-nitroimidazole benznidazole (BENZO) has previously been shown to be an effective potentiator of the cytotoxicity of CCNU in mice, at levels which are achievable in man. This enhancement is greater than that for normal tissues, resulting in a therapeutic gain. In this study BENZO has been given to 46 patients in oral doses of 4 mg/kg to 30 mg/kg, and drug concentrations measured in plasma, urine, tumor and normal brain by HPLC. The mean plasma t 1/2 was 12.8 +/- 0.5 h and plasma peak concentration and AUC0-infinity were linearly related to dose over the whole range. Approximately 60% of the drug was bound to plasma proteins and 6% excreted unchanged in urine. Mean tumor/plasma ratios of 88% (range 54 to 122%) for 11 gliomas and 72% (range 46 to 103%) for 6 superficially accessible non-brain tumors were obtained while that for normal brain was 69% (range 53 to 75%). Doses of more than 17 mg/kg BENZO produce changes in the plasma pharmacokinetics of CCNU (130 mg/m2 p.o.), increasing the half life of active hydroxylated metabolites. In addition, CCNU parent compound is present. This is not seen when CCNU is given alone. Such changes may result in improved response rates as it is possible to achieve in man, plasma and tumor levels of BENZO, which in the mouse model produce effective enhancement of the response to CCNU. No evidence was seen that BENZO enhanced wither the acute gastrointestinal toxicity or the hematological toxicity of CCNU over the dose range studied.

Drug Evaluation↗