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PubMed1976

The effect of dibromodulcitol on the template activity of DNA chromatin and nuclei from Yoshida sarcoma cells.

It has been shown earlier that after in vivo administration, dibromodulcitol (DBD) reacts with DNA and to a greater extent with chromosomal proteins of Yoshida sarcoma cells. The present experiments were designed to show if the binding of DBD to the chromatin elements of Yoshida sarcoma cells causes any changes in RNA synthesis using either DNA or chromatin as template in bacterial RNA polymerase system. During 4 to 24 h following in vivo administration, DBD reduces the template activity of dna without detectable single-strand breaks in the template DNA in alkaline sucrose gradients. Using chromatin as template the same dose of DBD produces no or very slight inhibition of RNA synthesis. Measuring the DNA-dependent RNA synthesis in nuclei isolated from Yoshida cells of treated rats, the dose of DBD which markedly inhibited the template activity of DNA, resulted in a significant stimulation of the nuclear RNA synthesis. The increased RNA synthesis was not due to an inhibition of ribonuclease activity. The observed alterations of the transcriptive properties of chromatin and nuclei produced by DBD are interpreted as being due to a modification of the whole nucleoprotein structure caused by the interaction of DBD with both DNA and chromosomal proteins.

Animals↗
PubMed1976

The effect of dibromodulcitol on resting and dividing lymphoid cells.

The effect of dibromodulcitol (DBD) on the incorporation of labelled precursors into DNA and RNA fractions of PHA-stimulated human lymphocytes and of P388F lymphoma cells at various stages of their growth was studied. Both cell systems showed sensitivity to the drug within the concentration rage of 1-10 mug/ml. When DBD was added before phytohaemagglutinin (PHA), h.han RNA. In contrast, by adding DBD after PHA, RNA labelling was much more inhibited than DNA. In the latter case, the decrease in DNA labelling occurred only 24 h after drug treatment whereas RNA labelling was decreased 1 h after treatment. Levels of DBD which normally produced 30% inhibition in plating efficiency of P388F lymphoma cells affected uridine-5-T incorporation to a different extent at different stages of growth of the culture. Enhanced RNA labelling occurred in early exponential stage while at later stages of growth, RNA synthesis was depressed.

Adult↗
PubMed1979

Chromatin proteins as a possible target for antitumour agents: alterations of chromatin proteins in dibromodulcitol treated Yoshida tumors.

The effect of dibromodulcitol (DBD) on Yoshida sarcoma chromatin components has been investigated. Measurements on the radioactivity of nuclear components after in vivo treatment with [3H]DBD for 1 h indicated preferential drug binding to the high molecular weight component of the nuclear residual acidic protein (non-histones) and also to Histone 1 (H1) (very lysine rich, F1). Two-hour DBD treatment resulted in partial degradation and reduced [3H]leucine incorporation into the same fractions of chromatin. However, 6 h after DBD treatment, the synthesis of the degraded chromatin proteins began and by 24 h was completed. During the same treatment period the composition of chromatin showed a remarkable alteration; 2 h after DBD treatment the amount of the nuclear residual acidic proteins relative to DNA decreased by approx. 50%, but returned to control value 24 h after drug treatment. This in conjunction with the data on [3H]leucine incorporation suggests that certain chromatin proteins are degraded and subsequently newly synthesised after DND treatment resulting in an exchange of chromatin components. The formation of a nucleohistone complex between H1 and DNA was inhibited by pretreatment of H1 and DBD, dianhydrodulcitol (DAD) and bischloroethylnitrosourea (BCNU).

Animals↗
PubMed1983

Identification of guanine and adenine adducts in DNA alkylated by dibromodulcitol in vitro and in vivo.

DNA reacted with dibromodulcitol in neutral solution yielded 3- and 7-alkyl substituted purines after hydrolysis at neutral pH-value at 37 degrees C. The alkylated products were identified by mass spectrometry and by comparison of their UV absorption spectra and chromatographic properties on thin-layer chromatography (TLC) and various columns with those of the corresponding galactitylpurine derivatives obtained by synthetic route from alkylation of the appropriate nucleic bases or nucleosides. The labelled alkylpurines occurring in DNA of Yoshida tumour cells treated with [3H]dibromodulcitol in vivo were also identified by co-chromatography of labelled DNA hydrolysate with synthetic 3- and 7-alkyl substituted purines. On the basis of the same chromatographic behaviour 3-(1-deoxy-3,6-anhydrogalactit-1-yl)adenine, 7-(1-deoxygalactit-1-yl)guanine, 7-(1-deoxy-3,6-anhydrogalactit-1-yl)guanine and 1,6-di(guanin-7-yl)-1,6-dideoxygalactitol were identified as main alkylated products in tumor cell DNA after in vivo treatment with dibromodulcitol.

Adenine↗
PubMed1985

Potentiation of antimetabolite action by dibromodulcitol in cell culture.

The postulation that the activity of key enzymes that reveal marked increases should be potential targets for anticancer chemotherapy (47) was supported by new evidence on the alterations of CDP reductase, CTP synthetase and OMP decarboxylase in hepatoma 3924A cell cultures. Inhibitors of these enzymes (VF-122, acivicin, pyrazofurin) and that of IMP dehydrogenase (tiazofurin) efficiently killed hepatoma 3924A cells in culture, as demonstrated by the clonogenic assay. Acivicin, pyrazofurin, tiazofurin and VF-122 were lethal against tumor cells in the exponential phase of growth with IC50 of 1.5, 5, 10 and 4.5 microM, respectively. All these antimetabolites exhibited cytotoxicity preponderantly against exponential-phase cultures, indicating that all the four drugs belong to Class II (phase-specific agents) in the Kinetic Classification of Anticancer Agents (38). Dibromodulcitol, a bifunctional alkylating agent, revealed cycle-specific cytotoxicity (Class III agent) against hepatoma 3924A, yielding IC50 values of 2.3 and 5.5 microM for exponentially and stationary growing cells, respectively. Using isobologram analysis on the survival data of 3924A cells, synergistic interaction was observed when DBD in combination with acivicin, pyrazofurin and tiazofurin was examined. DBD in combination with VF-122 exhibited additive lethality against hepatoma cells in culture. The synergistic and additive cytotoxicity in combinations of DBD with these antimetabolites was accompanied by the concurrent depletion of ribonucleotide and/or deoxyribonucleotide pools. The synergistic biological results of drug combinations of acivicin with DBD can be accounted for by the action of acivicin in inhibiting CTP synthetase, resulting in a synergistic decrease in CTP content, and by inhibition of DNA synthesis caused by DBD. The synergistic and additive depletion of UTP, CTP, dTTP and dCTP pools in the combinations of DBD with pyrazofurin may be responsible for the synergistic lethality of these combinations. Synergism, in terms of pool depletion, was observed for GTP and dCTP; summation was detected for dGTP when DBD and tiazofurin were given concurrently. The synergistic cytotoxicity of this drug combination may be a consequence of these alterations. The additive lethality of DBD-VF-122 drug combinations was reflected in the additive elevations of the ribonucleoside diphosphate concentrations. These observations indicate that treatments based on the Kinetic Classification and on the biochemical targeting of the drug should have an impact on the design of in vivo chemotherapy.

Amides↗
PubMed1987

Randomized phase III trial of single versus multiple chemotherapeutic treatment following surgery and during radiotherapy for patients with anaplastic gliomas.

In 81 patients with anaplastic supratentorial gliomas, single versus multiple chemotherapeutic agents were selected for treatment following surgery and during radiotherapy in a prospective randomized study. Time to treatment failure and survival were not significantly enhanced by multiple agent chemotherapy, as administered in this study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1982

Metabolism and pharmacokinetics of dibromodulcitol (DBD, NSC-104800) in man--II. pharmacokinetics of DBD.

Dibromodulcitol (DBD), labelled with [3H] at position C-1, was administered orally to 6 patients in a single dose of 15 mg/kg. Kinetic parameters were calculated for the effective drug (DBD + BrEpG + DAG), protein-bound hexitol moieties and free metabolites. Approximate values were estimated for the oral bioavailability of DBD. Disposal of the drug by metabolism and excretion was described by a simplified catenary model. The results indicated that 8-20% of the drug became firmly bound to macromolecules, probably by alkylation. The slow rate of alkylation in vivo (half-life 14 hr) may imply conversion of DBD into epoxides and their alkylating interaction with the target nucleophiles. The long retention of the firmly bound hexitol moieties in the body may be an indicator of the cumulative potency of DBD and must be taken into consideration by developing dosage schedules.

Administration, Oral↗
PubMed1982

Toxicity, antitumour and haematological effects of 1,2-anhydro-6-bromogalactitol and d-mannitol: a comparison with the related dibromo- and dianhydro-derivatives.

1,2-Anhydro-6-bromo-6-deoxygalactitol (BrEpG) and its D-mannitol analogue (BrEpM) intermediary metabolites in the conversion of dibromodulcitol (DBD) and dibromomannitol (DBM) into dianhydrogalactitol (DAG) and dianhydromannitol (DAM) have been prepared. The three types of derivative of each hexitol have been compared in their toxicities towards mice, tumour inhibitory activities against the Walker carcinosarcoma and haematological effects in rats. The bromoepoxides showed intermediate potency in all tests. The galactitol derivatives were always more potent than their mannitol counterparts. The mannitol derivatives were selectively myelosuppressive, being twice as toxic towards granulocytes as towards lymphocytes. The lymphotoxic activity of DBM, in particular, relative to its other toxic effects was particularly mild. These differences have been ascribed principally to the more rapid reactivity of DAG compared with DAM towards target nucleophiles, modulated by the influence of the bromine substituent on the transport properties of the dibromo- and bromoepoxy-derivatives.

Animals↗
PubMed1984

Dibromodulcitol, mitomycin C and vinblastine (DMV) chemotherapy in advanced breast cancer.

A combination of dibromodulcitol 500 mg orally, mitomycin C 10 mg i.v. and vinblastine 10 mg i.v. all given on day 1 and repeated every 4 weeks was given to 40 patients with advanced breast cancer. All but one had received previous endocrine therapy. The response rate (CR + PR) in 24 previously untreated patients was 66% and was 37% in 16 previously treated patients. The survival of responders was significantly longer than non-responders. Thirty-two per cent of patients experienced nausea and vomiting. There was little myelosuppression or thrombocytopenia on the day of starting a new course of therapy but the haemoglobin dropped by 2 g/dl in 32% of patients during therapy. Thus DMV is a relatively non-toxic active regimen for patients with advanced breast cancer.

Adult↗
PubMed1985

Rat liver-mediated degradation of dibromodulcitol.

The rate and extent of dibromodulcitol (DBD) conversion by 9000 g rat liver supernatant with an NADPH-generating system (S-9 mix) were studied using 3H-labelled drug. Results indicated that S-9 mix seemed to exert an initial protective effect delaying the solvolysis of DBD for about 30 min at 37 degrees C followed by rapid degradation into exclusively pharmacologically inactive products. Thus S-9 mix contained merely DBD as an effective agent; it amounted to less than 40% of the total radioactive compounds by 120 min. In the control mixtures the sovolytically produced effective drug content, i.e. the sum of DBD, 1,2-anhydro-6-bromo-6-deoxygalactitol (BrEpG), 1,2-5,6-dianhydrogalactitol (DAG) was 63%. Our results suggest the involvement of liver enzymes in the detoxification of DBD into inactive products. Therefore the antitumour effect of DBD cannot be attributed to its active BrEpG and DAG alone. The drug in its unchanged form may contribute to a somewhat greater extent to its cytostatic action than was believed before.

Animals↗
PubMed1986

Pharmacokinetics and metabolism of dianhydrogalactitol DAG in patients: a comparison with the human disposition of dibromodulcitol DBD.

Dianhydrogalactitol (DAG), labelled with 3H, was administered in single intravenous or oral doses to six patients (three in each group) with cancer. Kinetic parameters were calculated for the unchanged DAG and its biotransformation products. Elimination of the drug by metabolism and excretion was described by a catenary model. In order to elucidate the role of DAG as a mediator of the alkylating action of the cytostatic drug dibromodulcitol (DBD), the pharmacokinetic parameters of DAG and DBD were compared. The mean residence time for pharmacologically active molecules in the body was six times shorter for DAG (1.9 hr) than for DBD (11.4 hr). Alkylating action and metabolic degradation proceeded about 8-9 times faster for DAG than for DBD. The process of DBD alkylation implies a slow solvolytic conversion of the parent drug into the more reactive bromoepoxide and DAG. The preformed DAG would be rapidly consumed by intracellular alkylation and degradation, while unchanged DBD could form a depot in the cells and exert its cytostatic activity through the epoxides released in situ by solvolytic activation. Thus DBD entering the cells in unchanged form may have a more important role in its therapeutic effects than had been assumed earlier.

Adult↗
PubMed1990

The distribution of bromine content of dibromodulcitol in the central nervous system of patients with malignant gliomas.

The bromine content of human gliomas and white matter was determined by neutron activation analysis (NAA) following p.o. administration of a single dose of 400-500 mg/m2 dibromodulcitol (DBD). In another group of patients with brain gliomas, the bromine content was measured subsequent to application of a single dose of 334 mg/m2 of sodium bromide (equivalent dose regarding the bromine content of DBD). The bromine content of these two groups was compared to the values found in a third control group of untreated patients. The amount of bromine after DBD application was three to four times higher than in the untreated samples and the average accumulation ratio of 1.8 +/- 0.4 proved to be nearly identical both in tumour and white matter. The bromine values after NaBr treatment showed a different pattern of distribution. The accumulation was higher in the tumour tissue than in the normal white matter. These findings demonstrate that the pharmacokinetic properties of DBD- and NaBr-derived bromine are different, suggesting that the increase of bromine after DBD administration could be due to covalently bound bromine in DBD.

Brain Chemistry↗
PubMed1983

The distribution of [3H]-dibromodulcitol in the central nervous system of patients with brain tumour.

The uptake of [3H]-dibromodulcitol ( [3H]-DBD) into glioblastomas, white matter and cerebrospinal fluid was studied in 10 patients. Single-tissue samples were taken from different subjects at 4, 15 and 24 hr after [3H]-DBD administration. The level of 3H-compounds in the central nervous system was similar after a single (400 mg/m2), or 3 smaller daily oral doses of 150-180 mg/m2 of [3H]-DBD. The distribution of radioactivity was uniform in the tumour, white matter and muscle. Between 3 and 15 hr after administration of DBD the concentration of radioactivity did not change significantly and was between 5 and 13 micrograms of DBD/g tissue wet wt. At the same time the level in the cerebrospinal fluid (CSF) remained between 1 and 4 micrograms/ml. Meanwhile, the average concentration of radioactivity in the plasma fell from 11 to 3 micrograms/ml. The elimination half-life of the labelled compounds from the tissues was about 1 day as judged from the limited number of non-serial data obtained 4 and 24 hr after the last dose of repeated drug administration.

Administration, Oral↗