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PubMed2005

Interstitial transfer factor as adjuvant immunotherapy for experimental glioma.

Glioblastoma multiform (GBM) is the most common tumour of the central nervous system in humans. Unfortunately its prognosis is poor and because of the lack of efficacious therapies, immunotherapy is a potential treatment. Transfer factors (TF) are low molecular weight dialysable products extracted from immune cells which transmit the ability to express delayed-type hypersensitivity and cell mediated immunity from sensitized donors to nonimmnune recipients. In this study, we determined the efficacy of TF as immunotherapy to treat experimental glioblastoma. We used TF obtained from immunized swine. We evaluated different doses of intratumoral TF (product of 4x10(6), 8x10(5) and 1.6x10(5) cells). The best dose (product of 4x10(6) cells) of TF was also combined with carmustine for experimental therapy in rats with C6 malignant glioma. Modifications in peripheral blood T lymphocyte counts ( CD2+, CD4+, CD8+ and NK) were evaluated by flow cytometry. Cytokine expression in the tumour was assessed by RT-PCR and apoptosis was evaluated using the sub G0 method. Intratumoral TF reduced significantly the tumour size, and increased CD2+, CD4+, CD8+ and NK cell counts, it also increased the percentage of apoptotic tumour cells and the percentage of tumour tissue expressing Th1 cytokines. We observed an additive antitumoral effect when TF was combined with chemotherapy.

Animals↗
PubMed1991

Multifactorial mechanisms associated with broad cross-resistance of ovarian carcinoma cells selected by cyanomorpholino doxorubicin.

The cyanomorpholino derivative of doxorubicin (MRA-CN) is a DNA intercalator and alkylator that is a highly potent cytotoxin, non-cross-resistant in multidrug-resistant cells, and noncardiotoxic in comparison with doxorubicin. To further examine mechanisms of action and resistance to MRA-CN, a cell line resistant to MRA-CN, ES-2R, was established by growing a human ovarian carcinoma cell line, ES-2, in increasing concentrations of the drug. The resistant subline was 4-fold resistant to MRA-CN and cross-resistant to other DNA cross-linking agents, cisplatin (7-fold) and carmustine (3-fold), as well as to the DNA strand-breaking agents etoposide (6-fold), doxorubicin (2-fold), bleomycin (5-fold), and ionizing radiation (2-fold). In contrast, ES-2R cells were not cross-resistant to vinblastine. Several months of additional growth of ES-2R cells in MRA-CN did not yield higher, stable levels of drug resistance. A low level of P-glycoprotein was detectable in the ES-2R cells. However, the extent of intracellular accumulation of [3H]MRA-CN by this resistant cell line was identical to that of the sensitive line. The number of DNA cross-links formed by cisplatin in ES-2R was only 50% of that of the ES-2 cells and was associated with a 50% increase in the rate of repair of these cross-links in the resistant cells. Ionizing radiation induced similar amounts of single- and double-strand breaks in the ES-2 line as well as in the ES-2R cells. There was no apparent difference between the two cell lines in the rate and extent of repair of these DNA breaks. Thus, enhanced DNA repair cannot explain the phenomenon of cross-resistance to radiation. Comparisons of glutathione (GSH) content and the enzymes involved in GSH homeostasis showed significant differences. Resistant cells contained 1.5-fold more GSH, a 2.2-fold increase in gamma-glutamyltranspeptidase activity, and a 2.4-fold increase in GSH reductase compared with ES-2 cells (all P less than 0.05). Total glutathione-S-transferase (GST) activity was 2.6-fold higher (P less than 0.01) in the ES-2R line. The pi-class GST subunit by Western blotting and GST activity toward ethacrynic acid were increased 2-fold in the resistant cells. Depletion of GSH levels in ES-2R cells by buthionine sulfoximine restored the sensitivity of ES-2R to MRA-CN. These findings implicate a role for GSH metabolism in the resistance phenotype of ES-2R cells. We have previously reported that these cells have an increased generation time and decreased topoisomerase II content. Thus, the ES-2R cell line exhibits a complex phenotype of broad cross-resistance, which is likely to involve multiple mechanisms, and includes enhanced DNA repair and increased GSH content and GST activity.

Bleomycin↗
PubMedDate not supplied

Chemosensitivity spectrum of a human pleural mesothelioma xenograft grown in athymic rats.

A human pleural mesothelioma tumour line (AKG) serially transplantable as a subcutaneously growing xenograft in athymic rats was evaluated for chemosensitivity to six antitumour drugs. Drug effects were assessed as the reduction of the area under the tumour volume curve (1-AUC) and as specific growth delay (SGD), resulting from the maximum tolerable dose (MTD) intraperitoneally in athymic rats. SGD greater than 2 or (1-AUC) greater than 0.85 were used as criteria of an active drug at the MTD. Etoposide (40 mg/kg), vincristine (0.9 mg/kg) and vindesine (0.8 mg/kg) were found to be inactive. Cisplatin (CDDP; 8 mg/kg) and carmustine (BCNU; 40 mg/kg) were found to be active resulting in (1-AUC)s of 1.04 and 0.88, respectively. Although mitomycin C (MC) at the MTD of 1.8 mg/kg resulted in a (1-AUC) of only 0.81, the SGD at a dose of 1.5 mg/kg was greater than 2 and therefore the drug was regarded as active. Furthermore, a combination of CDDP 3 mg/kg and MC 1.25 mg/kg was found to be active resulting in (1-AUC) = 0.90 and SGD = 4.70. The combination of CDDP and MC seems to be a promising regime warranting further studies.

Animals↗
PubMed1991

[Chemotherapy and immunomodulating treatment of patients with multiple myeloma].

Prospective studies were carried out on the effectiveness of various treatment methods in 208 patients with plasmocytic myeloma. In 102 patients induction therapy was based exclusively on melphalan, in 106 cases polychemotherapy was used including vincristine, melphalan, carmustine, cyclophosphamide and prednisone. The differences in the per cent of patients with good response to treatment and in the survival time after treatment beginning were statistically not significant between these groups which suggests that polychemotherapy begun from the diagnosis of the disease is justified in patients with large mass of the neoplasm and poor prognostic factors. In 45 patients chemotherapy was supported by administration of immunomodulatory agents, including calf thymus extract in 25 cases, levamisole in 18 and interferon in 2. It was observed that maintenance of remission with chemotherapy and with immunomodulatory agents calf thymus extract or levamisole prolonged the survival of the patients. In cases of leucopenia the use of calf thymus extract facilitated chemotherapy by stimulation of myelopoiesis.

Adult↗
PubMed1991

[Brain metastases of malignant melanomas].

Cerebral metastases of malignant melanoma are correlated with a very poor prognosis. Surgery of an isolated metastase can lead to a long survival but the brain lesions are frequently numerous and associated with an extracerebral diffusion. Dacarbazine (DTIC) gives a mean response rate of 21% on visceral localisations but doesn't cross the blood brain barrier (BBB). Neither do the biological response modifiers like Interleukin 2 (Il2) that leads to 25% response rate in disseminated melanoma. Nitrosoureas like carmustine (BCNU) and semustine (CCNU) have been investigated in different non randomised studies and the clinical results didn't illustrate their theorical ability to cross the BBB. Radiotherapy is also used as a palliative therapy with 7 to 16 weeks survival. Fotemustine (muphoran), a new amino acid linked nitrosourea, can give a response rate up to 28.2% in patients with cerebral metastases and the increased survival of responding patients is significant. The availability of this new drug may suggest associations with surgery and radiotherapy in the future to improve the survival of such patients.

Antineoplastic Agents↗
PubMed1991

Sequential chemoimmunotherapy for metastatic melanoma.

Since February, 1990 we have evaluated a sequential form of chemoimmunotherapy as an investigative method for the treatment of metastatic melanoma. A cycle of therapy consisted of: carmustine (150 mg/m2) on day 1, dacarbazine (220 mg/m2) and cisplatin (25 mg/m2) on days 1 through 3 and 22 through 24, interleukin-2 (1.5 x 10(6) IU/m2 every 8 hours) and alpha-interferon (IFN alpha) (6.0 x 10(6) IU/m2 subcutaneously once daily) on days 4 through 8 and 17 through 21, and tamoxifen 10 mg orally twice daily for 6 weeks. Patients were evaluated for response 2 to 3 weeks after completing each cycle of therapy. Thirty-nine patients had been entered into this trial as of December 1, 1990, and 25 had completed at least one cycle of therapy and have been evaluated for response. The responses are as follows: complete response, six of 25 (24%); partial response, nine of 25 (36%); minor response, one of 25 (4%); stable disease, eight of 25 (32%); and progressive disease, one of 25 (4%). Median response duration has not been reached but is at least 5 months. Immunologic alterations associated with response and associated toxicity data will be presented.

Adult↗
PubMed1986

Chemosensitivity testing in V79 spheroids: drug delivery and cellular microenvironment.

Chinese hamster V79 multicell spheroids growing in tissue culture exhibit many of the same properties as solid tumors outgrowing their blood supply, including the spontaneous development of both noncycling and hypoxic cell populations expected to be resistant to many chemotherapeutic agents. Cell-sorting techniques were used to select cells as a function of their position (depth) within the spheroid to test this prediction. "Sensitivity profiles" of cells from various regions within spheroids after treatment with doxorubicin, bleomycin, 5-fluorouracil, carmustine, cisplatin, chlorambucil, and mitomycin are presented. Additionally, exposure of preseparated cells was used to distinguish inherent sensitivity from environmental or locational factors. For these drugs, penetration was a problem only for doxorubicin; in contrast, the microenvironment in the intact spheroid had a much greater influence on cell sensitivity.

Animals↗
PubMed1989

High dose chemotherapy with autologous hematopoietic stem cell support in the treatment of refractory stage IV breast carcinoma.

Fourteen patients with refractory metastatic breast cancer were treated with high dose chemotherapy and autologous hematopoietic stem cell rescue. All patients received cyclophosphamide (7.5 g/m2 over 3 days) and thiotepa (150-225 mg/m2 over 3 days), three patients in addition received melphalan (4.5 mg/kg), and seven patients received carmustine (150-562 mg/m2). Toxicities included pancytopenia, infection, hemorrhagic cystitis, skin rash, nausea, vomiting, diarrhea, and mucositis. There was one toxic death secondary to sepsis and ventricular tachycardia. The overall response rate was 77% including a 15% complete response rate. The overall median survival for all patients was 6.0 months (range 2-22 months). The median survival for nonresponders was 3.5 months. The median duration of response was 89 days (range 40-262). In our experience high dose chemotherapy with autologous stem cell reinfusion produces a high response rate in refractory breast cancer. However, because of the short duration of response and overall survival, we feel this type of therapy should be utilized earlier in the course of disease.

Adult↗
PubMed1989

Treatment of multiple myeloma by high dose chemotherapy, total body irradiation and autologous blood stem cell autograft.

Fourteen patients with stage III aggressive multiple myeloma were treated by high dose chemotherapy (carmustine, etoposide and melphalan) and total body irradiation. This procedure was followed by autografting using blood stem cells previously collected by leukapheresis performed during recovery of cytotoxic drug-induced bone marrow aplasia. One patient died from cerebral bleeding at day 40. All other patients, including 9 whose disease was refractory to conventional treatments, achieved an impressive tumor mass reduction (over 90% in 12 cases). Two patients relapsed and died 12 and 15 months after the graft; another one relapsed but is still alive at 24 months. Two to 23 months (median 12 months) after the autograft, 10 patients are well either in apparent complete remission (2 cases) or with a state of stable minimal residual disease. Autologous blood-derived hematopoietic stem cells induced successful and sustained engraftment in the 13 evaluable patients. The cells collected by leukapheresis were studied for clonal Ig genes rearrangements indicative of circulating tumoral cells (or clonal B precursors) and none were found. Although preliminary, these results appear promising and high dose chemotherapy followed by autologous blood stem cell graft deserves consideration in young patients with multiple myeloma.

Adult↗
PubMed1989

High-dose, potentially myeloablative chemotherapy and autologous bone marrow transplantation for patients with advanced Hodgkin's disease.

Twenty three patients with Hodgkin's disease were treated with BCNU (carmustine), etoposide, and cyclophosphamide at doses of 450-600 mg/m2, 1500-2000 mg/m2, and 120 mg/kg respectively. Bone marrow refrigerated at 4 degrees C for 2-5 days or cryopreserved at -80 degrees C was used to reconstitute bone marrow function. The median age was 28 (range 16-48), and the median Karnofsky performance status was 70. Nineteen patients had progressive disease while on chemotherapy. The median number of prior regimens was three (1-7), and the median number of prior chemotherapy drugs was 10 (range 4-12). Ten patients had received at least two of the drugs used in this study and four had had all three. Indicator lesions included lung (10), peripheral lymph nodes (9), retroperitoneal nodes (8), liver (3), and chest wall masses (2). Ten patients achieved a complete remission (43.5%; 95% confidence limits 23-64%), and five patients had a partial remission (21.7%; 95% confidence limits 5-39%). The median duration of complete remission was 6 months (range 2-13+ months). Responses were shorter in duration for patients with primary refractory disease. Liver function abnormalities were noted in nine (39%) cases. Post transplant, the recovery time was 18 days (range 11-43) for WBC and 24 days (11-77) for platelets. Two patients died of septic episodes while neutropenic. The median number of RBC units used was seven (range 1-45). Ten patients had evidence of pulmonary dysfunction. In seven patients there was symptomatic improvement with steroid therapy, but three patients who were not treated with steroids died as a result of interstitial pneumonia. Future programs should consider bone marrow transplantation in patients with Hodgkin's disease earlier in the course of disease, at the time of minimal residual disease, and employ newer, potentially less toxic drugs.

Adolescent↗
PubMed1989

Cross-resistance and glutathione-S-transferase-pi levels among four human melanoma cell lines selected for alkylating agent resistance.

A panel of four cell sublines, each selected for resistance to a different antineoplastic agent, has been developed from a human malignant melanoma cell line G3361. Following repeated exposure to escalating doses of the drug of interest, cloned sublines were developed that are 9-fold resistant to cisplatin (G3361/CP), 11-fold resistant to 4-hydroxyperoxy-cyclophosphamide (4-HC) (G3361/HC), 4-fold resistant to carmustine (BCNU) (G3361/BCNU), and 4-fold resistant to melphalan (G3361/PAM). The cross-resistance of each resistant cell line was determined for cisplatin, BCNU, 4-HC, melphalan, carboplatin, nitrogen mustard, and Adriamycin. In general, the alkylating agent-resistant cell lines were specifically resistant to the drug used for selection with the exception of the G3361/CP line, which was greater than 10-fold resistant to the cisplatin analogue carboplatin, 4-fold resistant to 4-HC, and slightly (1.5-fold) resistant to melphalan, and the G3361/BCNU line, which was slightly (1.8-fold) resistant to melphalan. Collateral sensitivity of the G3361/CP, G3361/PAM, and G3361/4HC lines to killing by BCNU was also observed. Glutathione-S-transferase activity was elevated in each of the alkylating agent-resistant cell lines by 3- to 5-fold with chlorodinitrobenzene substrate. On Western blotting, the glutathione-S-transferase-pi (GST-pi) isoenzyme protein was elevated in the resistant cells by 3- to 5-fold. A complementary DNA (pTS4-10) coding for GST-pi has been cloned from a lambda gt11 library, sequenced, and used as a probe to determine the relative levels of GST-pi mRNA in the alkylating agent-resistant cell lines. GST-pi mRNA levels were elevated (8- to 15-fold) in the resistant cell lines, indicating that the GST-pi increases were mediated through an increase in mRNA levels. GST-pi elevations are a frequent event in cells selected for alkylating agent resistance, and in some cases, of multiple drug resistance. However, the lack of cross-resistance among cell lines selected for resistance to different alkylating agents, all of which have elevated GST-pi levels, indicates that increased levels of GST-pi cannot be the predominate mechanism for resistance to the tested drugs in these cell lines.

Alkylating Agents↗
PubMed1988

New xenograft model for assessing experimental therapy of central nervous system tumors: human glioblastoma in the intrathecal compartment of the nude mouse.

Ten congenitally athymic "nude" mice and 10 immunocompetent mice underwent intrathecal inoculation with a human glioblastoma cell line (U87MG) via percutaneous lumbar puncture (5 x 10(5) cells/animal). All of the nude mice developed paraplegia with or without incontinence at 2 weeks and routinely died of inanition 3 weeks postimplantation. Histological examination confirmed extensive proliferation of neoplastic cells within the intrathecal space. A second group of animals was inoculated with 5 x 10(4) cells/animal: 20 nude mice, 10 cyclosporine A-immunosuppressed animals, and 10 immunocompetent control mice. The 20 mice were further divided into four subsets. Subset A did not receive chemotherapy, Subset B received 200 mg of carmustine (BCNU) per m2 by intraperitoneal injection, Subset C received a single dose of 4 mg of methotrexate (MTX) per m2 by intrathecal injection 4 hours after tumor inoculation, and Subset D received 12 mg of intrathecal MTX per m2. Decreasing the concentration of cells per animal by 1 log doubled the time interval required for the development of paralysis and incontinence to 4 weeks. Treatment with intrathecal MTX at a dose of 4 mg/m2 extended the symptom-free period by an additional week (to 5 weeks postinoculation), and a dose of 12 mg/m2 allowed an average of 6 weeks before the onset of neurological impairment. The xenografts did not grow in the immunocompetent control mice, the BCNU-treated group, or the cyclosporine A-immunosuppressed animals. An intrathecal xenograft model of central nervous system malignancies allows a novel approach to the evaluation of experimental chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Inhibition of neutrophil cytolysin production by target cells.

Neutrophils, triggered by heat-aggregated human IgG (Agg.IgG), were found to lyse chicken red blood cells (CRBC) as determined by a 51Cr release method. The lysis was inhibited by azide, catalase, chloride-free medium and amino acids, suggesting the requirement for myeloperoxidase (MPO), hydrogen peroxide (H2O2), chloride ions (Cl-), and hypochlorous acid (HOC1), respectively. These results indicate that neutrophils lyse CRBC through an HOCl-(ie, MPO-H2O2-Cl-) dependent process. Although HOCl can react with neutrophil-derived nitrogenous (N-) compounds to yield chloramines, the main and well-characterized chloramines did not play a direct role in the lysis of CRBC in our model system. Thus, it appears that lysis is due either to HOCl or to an unknown compound derived from and with characteristics similar to HOCl. When CRBC were replaced with HRBC targets, no lysis could be observed. Treatment of HRBC with carmustine, to inhibit the glutathione cycle, did not affect the cell resistance to lysis by neutrophils. Conversely, the inhibition of HRBC catalase activity with aminotriazole (AT) made the cells susceptible to neutrophil-mediated HOCl-dependent lysis: this suggests that HRBC escape lysis by neutrophils through an AT-inhibitable, ie catalase-dependent, process. Through an identical catalase-dependent process, HRBC were capable of efficiently preventing the H2O2 and HOCl recovery from Agg.IgG-triggered neutrophils, tested under experimental conditions similar to those used for cytolytic assays. Together, these data suggest that HRBC targets, endowed with high catalase activity, escape neutrophil-mediated lysis by consuming (by catalase) neutrophil-derived H2O2, so that HOCl cannot be produced in amounts sufficient to promote lysis. Parallel experiments, performed with AT-treated CRBC, showed that these cells, endowed with a relatively low catalase content, only partially limit neutrophil cytolytic efficiency by a process qualitatively similar to that observed with HRBC targets. The results provide evidence that target cells can restrain neutrophil cytolytic efficiency by interfering with the MPO-H2O2-Cl system through their catalase activity.

Amitrole↗
PubMed1987

DNA cross-linking responses of human malignant glioma cell strains to chloroethylnitrosoureas, cisplatin, and diaziquone.

Cell strains derived by culture of malignant glioma (astrocytoma grade III-IV) surgical specimens were tested for the production of DNA interstrand cross-links (ISC) and DNA-protein cross-links following treatment in vitro with 1-(2-chloroethyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine), 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea (PCNU), cis-dichlorodiammineplatinum(II) (cisplatin), and 3,6-diaziridinyl-2,5-bis(carboethoxyamino)-1,4-benzoquinone (diaziquone). ISC and DNA-protein crosslinks were measured by means of the DNA alkaline elution technique. Large differences among the cell strains were observed in DNA cross-linking responses to individual agents. The DNA responses to the chloroethylnitrosoureas, cisplatin, and diaziquone were largely independent of each other, except for a weak correlation between ISC responses to chloroethylnitrosoureas were distributed bimodally, in accord with a phenotypic distinction between Mer+ and Mer- cells. ISC responses to cisplatin and diaziquone showed significant variation among cell strains, but the distributions were not bimodal. The results demonstrate the existence of diverse DNA cross-linking response patterns among cell strains from different tumors of a given histological type.

Aziridines↗
PubMed1988

Results of recent salvage chemotherapy regimens for lymphoma and Hodgkin's disease.

From 1981 to 1983, 208 patients with recurrent or refractory lymphoma were treated with methylglyoxal-bis-guanylhydrazone (methyl-GAG), ifosfamide, methotrexate, etoposide (MIME). The complete remission (CR) rate was 24% and CR plus partial remission (PR) was 60%. Response was higher for aggressive than for indolent cell types. Median duration of CRs was 16.5 months and median survival of all patients was 9 months. In view of the in vitro synergism between cisplatin and high-dose cytarabine, we recently designed the DHAP regimen, which consists of cisplatin, 100 mg/m2 IV over 24 hours; cytarabine, 2 g/m2 IV over two hours every 12 hours for two doses; and dexamethasone, 40 mg orally daily for 4 days. There were 28 of 90 (31%) CRs and 22 of 90 (24%) PRs. Median duration of CR is 15 months; median survival of all patients is 6 months. The major toxicities have been infection (31%) and moderate to severe renal dysfunction (20%). In contrast to MIME, response rates did not differ significantly between aggressive and indolent cell types. A high-dose regimen (CBV) consisting of cyclophosphamide, 6 g/m2; carmustine, 300 mg/m2; and etoposide, 250 mg/m2 daily for 3 days followed by autologous bone marrow transplant (ABMT) has been successfully used to treat 62 patients with Hodgkin's disease recurrent or refractory after mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (MOPP/ABVD)-like regimens. A CR rate (47%) has been observed; 83% of these CRs remain alive and free of disease with a median follow-up of 19 months. This regimen appears to have curative potential in 40% of all cases and in 60% of cases treated after the first or second relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Potentiation of rat brain tumor therapy by fluosol and carbogen.

We have been using the 9L rat brain tumor model to investigate the effect of the combination of a perfluorochemical emulsion, Fluosol-DA 20%, and carbogen breathing on the therapy of brain tumors. The combination of Fluosol, carbogen breathing, and carmustine (BCNU) was more effective at prolonging survival than was BCNU alone. This difference was small but significant (P less than 0.25). neither Fluosol without carbogen nor carbogen without Fluosol significantly altered the effect of BCNU. Fluosol and carbogen alone did not affect the survival of tumor-burdened rats. Fluosol and carbogen breathing did not alter the effect of single doses of radiation on these tumors. This result supports the hypothesis that 9L brain tumors contain few, if any, critical hypoxic cells. However, these tumors may contain cells which are oxygen deficient but not radiobiologically hypoxic. The Fluosol-carbogen combination may be changing the intratumor environment in such a way that the metabolism or activity of BCNU is altered.

Animals↗
PubMed1988

Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group.

The Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial in patients with malignant gliomas to evaluate 4 treatment arms: 1) 60 Gy to the whole brain; 2) 60 Gy plus 10-Gy boost; 3) 60 Gy plus carmustine (BCNU); and 4) 60 Gy plus semustine plus dacarbazine. Between September 1974 and March 1979, 626 patients with malignant gliomas were treated on protocol RTOG 7401/ECOG 1374. Each institution chose a subset of the treatments to which the patients would be randomized. Patients were stratified according to subset and randomized to the 4 treatment arms. There were no differences in survival among treatment arms. For patients greater than 60 years of age, the addition of chemotherapy to radiation therapy did not improve survival. For patients aged 40-60 years, there was a statistically significant increase in overall survival when BCNU was added to 60 Gy (P less than .01), with an increase in 2-year survival from 8% to 23%. This beneficial effect of BCNU is apparent in both histological groups (astrocytoma with atypical or anaplastic foci and glioblastoma multiforme). Although few confirmatory autopsies are available, long-term survival in patients with astrocytomas with atypical and anaplastic foci who were treated with 60 Gy plus BCNU (5-yr survival, 22%) suggests no significant late CNS toxicity, compared to 60 Gy alone (5-yr survival, 15%). This is confirmed by comparable neurological function in long-term survivors.

Adult↗
PubMed1988

Response of cell subpopulations in spheroids to radiation-drug combinations.

Chinese hamster V79 cells grown as multicell spheroids were treated with radiation and/or selected antineoplastic drugs (5-fluorouracil, cisplatin, doxorubicin, mitomycin, and carmustine) administered at equitoxic levels in defined preirradiation and postirradiation sequences. Clonogenicity of the treated cells was determined, and the results from conventional assays were compared with those from cell-selection experiments, using a fluorescence-activated cell sorter, to determine the degree of interaction and regions of activity of the agents. Marked sequence-dependent differences in overall toxicity were observed; drug toxicity, spheroid reoxygenation, and direct sensitization appeared to be operative to a different extent with each drug and sequence. Maximal interaction between all drugs and radiation was, however, observed when drug exposure immediately preceded irradiation.

Antineoplastic Agents↗