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At least 955 records · Page 53Linked to original sources
PubMed1984

Hypoxic cells and in situ chemopotentiation of the nitrosoureas by misonidazole.

Intracerebral (i.c.) and subcutaneous (s.c.) 9L tumours were treated simultaneously with various doses of the nitrosoureas, BCNU or CCNU, and 2.5 mmol kg-1 of misonidazole (MISO). After 24 h, tumours were removed, dissociated into single cell suspensions and the cells plated for colony formation. In both i.c. and s.c. tumours, no cell kill was observed after exposure to MISO alone, and no additional cell kill was observed when MISO was combined with either nitrosourea. If s.c. 9L tumours were clamped 30 min after i.p. injection of 2.5 mmol kg-1 MISO, then 2 h later the clamps were removed and the nitrosourea injected, an increase in cell kill was observed. This increase in cell kill was statistically significant (P less than 0.01) for each dose of BCNU administered, but not statistically significant (P greater than 0.05) for the moderate dose of CCNU administered. Clamping did not alter the colony forming efficiency of cells from untreated 9L s.c. tumours or from those treated with each drug alone. These data demonstrate that hypoxic cells are required for misonidazole to potentiate the cell-killing effects of the nitrosoureas and that s.c. 9L tumours contain no such cells.

Animals↗
PubMed1984

Chemopotentiation in vivo: no loss of sensitization with fractionation.

The response of KHT sarcomas to one, two, five or ten daily fractions of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), with and without misonidazole (MISO), was evaluated using delay of tumour regrowth as the measure of response. When CCNU was given as 2 dose fractions separated by 24 h rather than as a single treatment, no extra dose was necessary to achieve a particular level of damage, suggesting a lack of damage repair. With increasing fraction number, however, an increasing total dose of drug was required to achieve a given effect, presumably to compensate for proliferation. Increasing drug doses also were readily tolerated (almost twice the LD50/7 for a single dose of CCNU resulted in no deaths when given in a 10 fraction treatment) indicating a large sparing of normal tissue toxicity when CCNU treatments were fractionated. The addition of MISO enhanced the tumour response to CCNU in all treatment schemes. When single doses of CCNU were combined with 0.5 mg g-1 MISO, an enhancement ratio (ER) of approximately 1.5 was observed. This ER was maintained for all fractionated treatment schedules including the 10 daily fraction protocol. In addition, no loss of sensitization with increasing fractionation was observed when a lower dose of 0.2 mg g-1 MISO was combined with each of 5 or 10 daily fractions of CCNU. Similar experiments were performed to test the combination of cyclophosphamide (Cy) and MISO (0.5 mg g-1) in the RIF-1 tumour; again chemopotentiation was maintained with increasing fractionation. These results of combined MISO and fractionated chemotherapy are in contrast to the rapid loss of sensitization observed when MISO is used as a radiation sensitizer and combined with small doses of X-rays, thus providing in vivo evidence of the mechanistic difference between the effects of MISO used as a radiation sensitizer or chemopotentiator. Peripheral white blood cell counts performed on mice receiving 5 daily fractions of CCNU +/- MISO displayed no significant enhancement of normal tissue toxicity by MISO. Thus combining MISO with repeated low dose treatments of a chemotherapeutic agent results in a therapeutic gain.

Animals↗
PubMed1984

Misonidazole and CCNU: further evidence for a pharmacokinetic mechanism of chemosensitization and therapeutic gain.

Detailed studies of the effects of misonidazole (MISO) on the pharmacokinetics of CCNU in the KHT tumour, bone marrow and the gut have been carried out in order to elucidate the mechanism of chemosensitisation by MISO, and the therapeutic gain often obtained due to the preferential enhancement of tumour toxicity. In experiments where CCNU concentration and growth delay were both measured in the same transplant group of tumours, we found that tumour response is well correlated with tumour peak CCNU concentration. Further, with MISO treatment the tumour peak CCNU concentration was increased such that the enhancement of tumour response can be entirely accounted for by this increase. The effects of MISO on the CCNU pharmacokinetics in bone marrow and in the gut were different from the tumour in that peak CCNU concentration was not increased. We suggest that this is the explanation for the therapeutic gain.

Animals↗
PubMed1985

Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU.

Because the nitrosourea CCNU is given exclusively by the oral route in man, we have carried out studies in mice on the antitumour activity, acute toxicity and pharmacokinetics of oral CCNU, either alone or in combination with the chemosensitizer misonidazole. In both plasma and KHT tumour the peak concentration and "early" AUC for total nitrosoureas were about 1.4-1.5 fold greater for the oral compared to the i.p. route. These differences were reflected in the roughly twofold greater antitumour activity for the oral route. In contrast, acute toxicity tests showed that oral CCNU was 1.45 times less toxic to normal tissue, although the dose-limiting organ may be different for the two routes. Misonidazole reduced the antitumour activity of oral CCNU by dose modifying factors (DMF) of 0.58-0.71. Similarly, the acute toxicity was also diminished by a DMF of 0.74. Misonidazole has a complex effect on oral CCNU pharmacokinetics. The plasma and tumour total nitrosourea peak concentrations were reduced by 1.5 and 1.7 fold respectively. Misonidazole also reduced the "early" nitrosourea AUC, with the extent of the reduction depending on the minimum effective concentration (MEC) chosen. For example, the plasma nitrosourea AUC was reduced by factors of 1.05 and 9.6 for MEC values of 1 and 2 micrograms ml-1 respectively. We propose these pharmacokinetic changes to be the underlying mechanism for the reduction of oral CCNU cytotoxicity by misonidazole. Clinical trials of such combinations should be accompanied by detailed pharmacokinetic evaluation.

Administration, Oral↗
PubMed1985

DNA repeat length in chromatin from murine bone marrow and L1210 leukaemia cells.

Previous studies have suggested that 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl) -3-nitrosoureahydrochloride (ACNU) and 1,(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) bind specifically to the nucleosomal DNA of murine bone marrow and L1210 leukaemia cells whereas the glucose nitrosoureas, 2-(3-(2-chloroethyl)-3-nitrosoureido)-2-deoxy-D-glucopyranose, (chlorozotocin, CLZ) and 1-(2-chloroethyl)-3-(-D-glucopyranosyl)-1-nitrosourea (GANU), bind preferentially to the linker DNA of bone marrow but not tumour cell chromatin. In order to provide an explanation for this differential, the DNA repeat and linker lengths in murine bone marrow and L1210 leukaemia cells were measured using electrophoresis of micrococcal nuclease-digested DNA. The linker length of bone marrow chromatin was approximately 22% longer than that in L1210 leukaemia cells from mouse ascites. The linker length of L1210 cells maintained in suspension culture was 27% less than in those from ascites fluid. The tissue-specific toxicity of sugar nitrosoureas and the differential binding of these drugs to chromatin does not appear to correlate quantitatively with differences in DNA linker length.

Animals↗
PubMed1985

The response to cytotoxic drugs of EMT6 cells treated either as intact or disaggregated spheroids.

We have compared the response to a number of cytotoxic drugs of cells treated either within intact multicellular spheroids or as isolated cells following spheroid disaggregation. The cells used were of the EMT6/Ca/VJAC mouse tumour line and spheroids were treated or disaggregated at a mean diameter of 250 micron. The response of cell to nitrogen mustard (HN2) or CCNU was similar under the two exposure conditions and we conclude that factors related to spheroid structure (i.e. drug penetrability, intercellular contact effect and microenvironment within the spheroid) do not influence the initial response to these agents. Recovery of potentially lethal damage occurring over 24 h, however, greatly modifies the level of cell killing in intact spheroids. EMT6 cells were found to be extremely resistant to vincristine under all exposure conditions. For adriamycin (ADM), cells were always initially more sensitive when exposed to the drug in suspension rather than in intact spheroids. When ADM exposure was prolonged beyond 1 h, however, delaying spheroid disaggregation for 24 h led to increased cell kill and reduced differential between the two conditions of exposure. The data suggest that both drug penetration problems and other factors related to spheroid structure are involved in determining the response of cells in small spheroids to ADM.

Animals↗
PubMed1985

Assay of anti-cancer drugs in tissue culture: relationship of relapse free interval (RFI) and in vitro chemosensitivity in patients with malignant cerebral glioma.

One hundred and seventeen patients with cerebral glioma (Kernohan grades III and IV) were treated with adjuvant chemotherapy using procarbazine (PCB), CCNU and vincristine (VCR) following whole head irradiation. Cell cultures were prepared from 40 patients in this series and their sensitivity to each cytotoxic drug was assessed in a mictotitration assay with 35 S-methionine incorporation as the end point. Twenty-two of forty (55%) patients responded to PCB and/or CCNU in vitro, and sensitivity to these drugs was linked with increased RFI, whilst sensitivity to VCR was not. The RFI of patients who had responded to PCB or CCNU in vitro was significantly longer than the RFI of patients whose tumours failed to respond in vitro or patients who had not been tested. There was no difference in sex ratio, extent of operation, radiation dose and degree of steroid cover between responders, non-responders and untested groups. Grade III tumours tended to be more sensitive in vitro than grade IV tumours. The age of patients also influenced in vitro chemosensitivity. Patients with chemosensitive tumours in vitro tended to be younger than patients with insensitive tumours in vitro. Further statistical analysis, taking into account these prognostic factors, indicated an association between chemosensitivity in vitro and RFI.

Adult↗
PubMed1986

Emergence of nitrosourea resistant sublines of Lewis lung tumour following MeCCNU treatment in vivo.

Several different drug retreatment protocols were employed to examine the emergence of resistance to MeCCNU in Lewis lung tumours. Previous studies suggested that although the majority of cells in untreated Lewis lung tumours were sensitive to MeCCNU, there was a very small proportion of resistant cells (approximately 0.001%) that limited "tumour cure' with that drug. If such cells were inherently drug resistant then it should be possible to derive highly resistant tumours by repeated drug treatment. In the first experiment tumours were treated with a single high dose of MeCCNU (35 or 40 mgkg-1) and on regrowth, transplanted into fresh mice and tested for drug sensitivity. Using both excision cell survival and growth delay endpoints, only approximately 25% of tumours were significantly resistant to the test dose, suggesting that many tumours resist the effects of the drug for reasons other than the presence of inherently drug resistant cells. One of the tumours (R4), that regrew after the initial treatment and appeared to be resistant to the test treatment, was retreated with a further 30 mgkg-1 MeCCNU and became more resistant. This line, designated R4/1, was cross-resistant to the other nitrosoureas, BCNU and CCNU, but not to cyclophosphamide, melphalan, cis-platinum or ionising radiation. The effect of treatment dose on the kinetics of MeCCNU resistance development was also studied in a retreatment regimen where the tumours were allowed to regrow and then transplanted into fresh hosts for the next treatment. Resistance developed more quickly at an intermediate dose of 15 mgkg-1 than at 7.5 mgkg-1 where the selective pressure was lower, or at 30 mgkg-1 where there was probably extinction of partially resistant cells. Resistance to MeCCNU developed even more quickly when tumours were retreated several times in the same host, although in a similar experiment with cyclophosphamide no resistance occurred.

Animals↗
PubMed1987

Chemosensitization by misonidazole in CCNU-treated spheroids and tumours.

Misonidazole has been demonstrated to enhance the cytotoxicity of several common antineoplastic drugs in vitro and in vivo, and its mechanism of action as a chemosensitizer, though still unknown, is thought to be dependent upon hypoxia. We have used fluorescence-activated cell sorting to evaluate chemopotentiation by misonidazole as a function of cell position in V79 spheroids and KHT tumours. CCNU toxicity was enhanced in all cell subpopulations of both tumours and spheroids, with greater consistency than might be predicted on the basis of the known variations in oxygen tension. Further, both misonidazole and CCNU as single agents were preferentially toxic in the less well oxygenated regions of each system, arguing that differential toxicity cannot be implicated in the chemopotentiation observed. In fact, increased treatment toxicity did not necessarily lead to increased chemopotentiation, nor was potentiation directly related to the metabolism/binding of the misonidazole. Chemopotentiation in multicell systems thus appears to be a complex, multi-factorial process.

Animals↗
PubMed1987

Use of a tritiated thymidine suicide technique in the study of the cytotoxic drug response of cells located at different depths within multicellular spheroids.

A technique using 'tritiated thymidine suicide' has been established as a means of studying the response to cytotoxic drugs of cells at different depths within multicellular tumour spheroids. Because of the characteristic spatial arrangement of cycling cells (mostly in the outer regions) and non-cycling cells (mostly at the inner regions) of spheroids, cells surviving after long term (24 h) exposure of spheroids to high doses of 3HTdR will be those located furthest from the surface. By comparing the drug response of cells from 3HTdR pre-treated and untreated spheroids, the individual response of total cells, cells near to the surface and cells lying deeper within the viable rim of spheroids can therefore be deduced. In this study, large spheroids of about 800 micron in diameter of a mouse mammary cell line, EMT6/Ca/VJAC, and of a human small cell lung cancer cell line, POC, have been used. Using clonogenic assay, the response of these two cell types to adriamycin (ADM), nitrogen mustard (HN2), CCNU and vincristine (VCR) (POC only) were measured. The preliminary part of this study has confirmed that the cells killed are those which incorporate 3HTdR during the DNA synthesis period; the cells killed are mainly located in the outer regions of spheroids i.e. surviving cells are mostly located in the inner part of the viable rim and 3HTdR pretreatment does not sensitise surviving cells to subsequent cytotoxic drug treatment. Results from large EMT6 spheroids agree with our previous findings (obtained using a selective disaggregation method) that cells in the outer regions of spheroids are more sensitive to ADM and HN2 than cells in the inner regions whilst the opposite is true for CCNU. For POC spheroids, cells in the outer region of spheroids are more sensitive to ADM and VCR than cells in the inner region whilst a reverse trend is seen for the response to CCNU. The response to HN2 is similar at all depths. Amongst the factors governing the response of cells in spheroids to cytotoxic drugs, the responses to ADM and VCR are thought to be largely dictated by cell cycle distribution and limited drug penetrability, whilst for HN2 the response may be determined by the factor of cell cycle distribution. For CCNU, we believe that the cellular response is largely dependent upon microenvironmental factors prevailing within spheroids.

Animals↗
PubMed1988

Predictive chemosensitivity testing in malignant melanoma: reliable methodology--ineffective drugs.

A retrospective and a prospective trial were carried out in patients with malignant melanomas to investigate the predictive value of an in vitro chemosensitivity assay based on the Courtenay and Mills soft agar cultivation method. Evaluable in vitro chemosensitivity data for the three agents DTIC, CCNU, and vinblastine were obtained in 153 cases. In the retrospective study in which the patients received chemotherapy without prior knowledge of the test results, 50 in vitro/in vivo correlations (40 patients) were made, and in the prospective study, where patients received the single agent most active in vitro, 55 correlations (45 patients) were performed. In both studies the sensitivity of the test (the ability to identify patients who will respond to chemotherapy) was approximately 100% and the specificity (the ability to identify patients who will not respond) was 87-98%. Depending on whether 'no change' and 'mixed response' were classified as sensitivity or resistance, the predictive value of a negative test was approximately 100% and that of a positive test 37.5-87.5%. The response rate was low in both series, and although it was somewhat higher in the prospective than in the retrospective trial, the difference was not significant. The median survival time was not significantly different in the two treatment series. We conclude that the chemosensitivity assay here used is reliable and has predictive value, but that the chemotherapeutic agents currently available for treatment of melanoma are too ineffective to warrant routine use of the assay in this disease.

Dacarbazine↗
PubMed1989

Influence of dose intensity and density on therapeutic and toxic effects in Hodgkin's disease.

From 1972 to 1976, 95 patients with clinical stages I-IIIA Hodgkin's disease were treated by chemotherapy with cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) before and after extended field radiotherapy. The CVPP schedule gave: (1) a constant drug dosage for each patient independent of body surface or weight; and (2) a total drug dosage dependent on haematological tolerance, since the treatment was given for 21 days or until the leukocyte count dropped to 2 x 10(9) l-1. The drug dosage per unit body surface (or 'dose density') significantly correlates with the drop in leukocyte count (P less than 0.001) and the tumour regression at the end of the induction course (P = 0.020). Disease-free survival is significantly related to dose density (P = 0.050) but not to dose intensity calculated on the duration of treatment (P = 0.240). However, after exclusion of three marginal recurrences due to border-line radiotherapy, the dose intensity significantly correlates with the disease-free survival (P = 0.031) and with the duration of complete remission (r = 0.870).

Adolescent↗
PubMed1989

Response to cytostatic treatment in inoperable adenocarcinoma of the lung: critical implications.

The prognostic factors for response to chemotherapy and the prognostic impact of response status on survival, relative to other prognostic variables, were evaluated among 53 responding (9 complete responses; 44 partial responses) and 165 non-responding patients with inoperable adenocarcinoma of the lung (ACL). Multiple logistic regression analysis, including 27 pretreatment variables, revealed that the only significant predictor of response was bidimensionally measurable disease parameter (P = 0.02), followed by brain metastases that were negatively correlated to response, although insignificantly (P = 0.10). Univariate landmark analyses among patients alive at 8, 12, 16 and 24 weeks showed a trend towards better survival for responders compared with non-responders, but did not reach a significant level at any time (P values 0.78, 0.57, 0.23 and 0.12, respectively). Death hazard ratios for responders to non-responders were 0.91, 0.89, 0.79 and 0.73. Multivariate regression analysis among patients alive at 16 weeks demonstrated a significant impact on survival for performance status, non-radical tumour resection, liver metastases and LDH, while the impact of response status in comparison was weak and insignificant. This reflects the unsatisfactory treatment results achieved in inoperable ACL, with the majority of responses being partial, and calls for improvement of the cytostatic treatment currently available.

Adenocarcinoma↗
PubMed1990

The chemotherapeutic response of a murine (VM) model of human glioma.

Using a cell line derived from the VM spontaneous murine astrocytoma, a reliable in vitro-in vivo model of human malignant glioma has been developed. In this paper we examine the effects of cytotoxic drugs with known activity against other animal brain tumour models and human disease on the in vivo VM model. The drugs BCNU, CCNU and vincristine produced significant volume reduction in tumours growing at a subcutaneous location in syngeneic animals. Procarbazine was ineffective. Similarly, BCNU, CCNU and vincristine produced small but statistically significant increases in survival of VM mice bearing the intracerebral tumour, but procarbazine was again ineffective. The modest, but significant, response of the VM model to the nitrosoureas mimics the human situation more closely than previously described animal models.

Animals↗
PubMed1990

Enhancement of chemotherapy and nitroimidazole-induced chemopotentiation by the vasoactive agent hydralazine.

Nitroimidazoles have been shown to be potent sensitisers of certain clinically active chemotherapeutic agents. This process of chemopotentiation has been shown to be hypoxia-mediated. The present studies evaluated whether increasing the level of hypoxia in the tumour tissue, by treatment with the vasoactive agent hydralazine, could modify the chemosensitising ability of nitroheterocyclics. Administering either misonidazole or RSU 1164 before, or hydralazine after, the chemotherapeutic agents melphalan, cyclophosphamide or the nitrosourea CCNU, increased the extent of cell kill in both the KHT sarcoma and RIF-1 tumour. However, even greater enhancements could be achieved when hydralazine was used in treatment protocols in which a nitroimidazole was combined with chemotherapy. For example, a 5.0 mg kg-1 dose of hydralazine given 30 min after melphalan, or a 2.5 mmol kg-1 dose of misonidazole administered 30 min before melphalan, increased, compared to melphalan alone, the resultant tumour cell kill by factors of approximately 1.9 and approximately 1.3, respectively. By comparison, when hydralazine was given after the melphalan plus misonidazole combination, treatment efficacy was enhanced approximately 3-fold compared to melphalan alone. Yet in contrast to the results of the tumour response studies, the inclusion of hydralazine did not increase the bone marrow toxicity associated with the chemotherapeutic agent when used alone or in conjunction with a nitroimidazole. The results, therefore, imply that the addition of hydralazine to the chemotherapy, or chemotherapy-sensitiser protocol, led to a therapeutic advantage.

Animals↗
PubMed1990

Cisplatin and CCNU synergism in spheroid cell subpopulations.

The cytotoxicity of two antineoplastic drugs, cisplatin and CCNU, was evaluated in Chinese hamster V79 multicell spheroids using the drugs as single agents or combinations. Cells obtained from different depths within spheroids 550-750 microns in diameter showed different sensitivities to the two agents; the external cells of the spheroids were more sensitive than the internal cells to cisplatin, whereas the internal cells were most effectively killed by CCNU. Combining the two agents produced the expected 'complementary' activity, and in addition, synergism was observed between the drugs at exposure levels practical for clinical use. For the combination treatments, both the net pattern of cell killing through the spheroid and the degree of interaction between the agents (quantified using the combination index method) were a function of the dose ratio of the two drugs, and of overall treatment intensity. BCNU produced patterns of cell killing similar to CCNU, but showed little interaction with cisplatin. Our results suggest significant clinical potential in using CCNU with cisplatin, particularly since CCNU-cisplatin combinations were synergistic even in the cell subpopulations most resistant to each drug as a single agent.

Animals↗
PubMed1990

Chemotherapy for malignant melanoma: combinations and high doses produce more responses without survival benefit.

In a consecutive series of studies, 164 patients with symptomatic and/or visceral metastatic malignant melanoma were treated with single agent vindesine, high dose melphalan with autologous bone marrow transplantation (AMBT), high dose BCNU with ABMT or the BOLD (bleomycin, vincristine, CCNU and DTIC) combination. The high dose treatments and the combination chemotherapy resulted in significantly higher response rates but no prolongation of survival. Factors associated with longer survival included the absence of visceral metastases, the absence of bulky disease and good performance status. For all treatments, life table estimates of survival at 1 and 2 years were only 10% and 4% respectively.

Adolescent↗