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Journal of Clinical Oncology : Official... May 1986A combined clinical and pharmacokinetic phase I study of the substituted hexitol dibromodulcitol (DBD), administered as a single oral monthly dose, has been performed....
A combined clinical and pharmacokinetic phase I study of the substituted hexitol dibromodulcitol (DBD), administered as a single oral monthly dose, has been performed. Twenty-three patients with advanced neoplasms received DBD doses ranging from 600 to 1,800 mg/m2 body surface area (BSA). The dose-limiting toxicity was myelosuppression, with both significant granulocytopenia and thrombocytopenia occurring at dose levels of 1,500 to 1,800 mg/m2. The average pharmacokinetic parameters for DBD, calculated on the basis of a one-compartment model with first-order absorption and elimination, include the elimination constant, .005 +/- .002/min; absorption constant, .012 +/- .009/min; and an apparent volume of distribution, 1.03 +/- .4 L/kg. The area under the drug concentration curve (AUC) and the peak drug level (Cmax) were linearly related to the dose administered (P less than .001). The mean AUC was 18.7 +/- 6.1 mmol/L min, and the mean Cmax was 47.1 +/- 16.8 mumol/L when normalized to a DBD dose of 1 gm/m2. The elimination constant was significantly reduced in patients with abnormal hepatic function (P less than .01). The elimination constant was not correlated with renal function. The half-life of DBD in plasma (158 minutes) was considerably shorter than the four-to eight-hour half-life of total radioactivity in plasma measured by previous investigators following the administration of radiolabeled DBD.
Topics: Absorption; Administration, Oral; Adult; Aged; Bone Marrow Transplantation; Carcinoma; Dianhydrogalactitol; Dose-Response Relationship, Drug; Drug Evaluation; Female; Half-Life; Humans; Kinetics; Male; Melanoma; Middle Aged; Mitolactol; Neoplasm Metastasis; Sarcoma; Time Factors
PubMed: 3517245
DOI: 10.1200/JCO.1986.4.5.753 -
British Journal of Cancer Feb 1995The efficacy and modes of action of dibromodulcitol (DBD) and cisplatin (CDDP) were studied in several model systems. Combination treatments produced a longer survival... (Comparative Study)
Comparative Study
The efficacy and modes of action of dibromodulcitol (DBD) and cisplatin (CDDP) were studied in several model systems. Combination treatments produced a longer survival time in mice bearing P388 solid lymphomas than either of the drugs alone. In the human metastatic melanoma HT-168 xenograft model the combined application of DBD and CDDP was also very effective, inducing a reduction in the number and volume of metastatic nodules. For V79 spheroids, DBD was mainly cytotoxic against the internal, quiescent cells, whereas cisplatin primarily killed cells in the proliferating, external regions of the spheroids. When combined, the drugs appeared to act synergistically throughout the spheroids. Studies on plasmid DNA showed that CDDP primarily generates cross-links, whereas single-strand breaks were dominant after DBD treatment. Upon using an assay for cleavage by restriction nuclease, antagonistic action of DBD and CDDP in combination may occur, nevertheless more strand breaks were always observed in these samples. These results suggest that the efficacy of combined DBD and CDDP is in part a result of 'spatial cooperation' by the drugs (i.e. affecting different cells) and in part the result of DNA damage produced by the combination treatments.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cisplatin; DNA Damage; DNA, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Leukemia P388; Male; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred DBA; Mitolactol; Neoplasm Metastasis; Neoplasm Transplantation; Tumor Cells, Cultured
PubMed: 7841047
DOI: 10.1038/bjc.1995.63 -
Progress in Neuro-psychopharmacology &... Jun 2009Depression and impaired quality of life (QOL) are frequently observed in patients suffering from a variety of diseases. In addition, it has been reported that an...
Depression and impaired quality of life (QOL) are frequently observed in patients suffering from a variety of diseases. In addition, it has been reported that an enhanced degradation of the serotonin precursor tryptophan may contribute to QOL deterioration in some diseases. However, it is unclear whether the correlation between the QOL scores and the central serotonergic tone is only mediated by the severity of either the depression symptoms or the physical illness itself. The present study examined the relationship between serotonin transporter (SERT) availability and life quality as measured by the World Health Organization Quality of Life brief version questionnaire (WHO-QOL) in healthy participants in order to exclude the influence of depressive mood and disease. The SERT availability in the midbrain was approximated using SPECT with [(123)I] ADAM ligand in fifty-eight healthy volunteers. The overall rating sub scores of the WHO-QOL correlated positively with serotonin transporter availability in the males. Central serotoninergic activity may play a role in the overall rating scores of the WHO-QOL.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Association; Brain; Doxorubicin; Female; Health Status; Humans; Iodine Isotopes; Male; Mitolactol; Mitomycins; Quality of Life; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Surveys and Questionnaires; Tomography, Emission-Computed, Single-Photon; Young Adult
PubMed: 19332100
DOI: 10.1016/j.pnpbp.2009.03.018 -
Cancer Treatment Reports Feb 1986The effects of four hexitol compounds [mitolactol, dianhydrogalactitol, 3,4-diacetyldianhydrogalactitol (DiacDAG), and 3,4-disuccinyldianhydrogalactitol]; two vinca... (Comparative Study)
Comparative Study
The effects of four hexitol compounds [mitolactol, dianhydrogalactitol, 3,4-diacetyldianhydrogalactitol (DiacDAG), and 3,4-disuccinyldianhydrogalactitol]; two vinca alkaloids (vincristine and N-formylleurosine); doxorubicin; and methotrexate on colony formation of P388 and K562 cells were studied and compared. DisuDAG is a new derivative of hexitols with favorable therapeutic indices on rodent tumors. On the basis of IC50 values in molar concentrations, dianhydrogalactitol was five to six times more toxic than DiacDAG, and mitolactol was 36 (K562) or 80 (P388) times more toxic than DisuDAG. N-Formylleurosine was found to be 20 (P388) or 1000 (K562) times less toxic than vincristine. The large difference was due to the high resistance of K562 cells to N-formylleurosine. Both cell lines were very sensitive to doxorubicin: IC50 after 1 hour of exposure of P388 cells = 240 nM and after 1 hour of exposure of K562 cells = 275 nM. Continuous exposure to methotrexate resulted in 11 and 14.5 nM for P388 and K562 cells, respectively. We have not found direct correlation between the length of doubling times and drug sensitivity (doubling time of P388 = 13-14 hours and of K562 = 25 hours). The sensitivity of cell lines was rather tumor-specific and drug-dependent.
Topics: Animals; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Leukemia; Leukemia P388; Leukemia, Experimental; Mice; Sugar Alcohols
PubMed: 3948192
DOI: No ID Found -
International Journal of Cancer Apr 1975In studies on a model of induced pulmonary metastasis in mice a tumour host system was analysed which was not affected by immunogenicity of the tumour for the host;...
In studies on a model of induced pulmonary metastasis in mice a tumour host system was analysed which was not affected by immunogenicity of the tumour for the host; neither intensive immunosuppression nor immunization caused a significant change in the quantity of pulmonary metastatic nodules. In contrast the application of cytostatic drugs and of Corynebacterium parvum could modify the pulmonary resistance to the formation of tumour nodules by a factor greater than 100 in either direction. This finding confirms the observation of others that major modification of the resistance to metastatic tumour formation can occur independently of classical immunological mechanisms. Special attention is drawn to the fact that cyclophosphamide enhances the formation of metastatic nodules in this model by factors of 100 to more than 1,000 whereas other cytostatic drugs including the cyclophosphamide congeners iphosphamide and trophosphamide are active only factors between 2 and 12. The possible practical significance of these findings is discussed.
Topics: Alkylating Agents; Animals; Antineoplastic Agents; Busulfan; Cell Transformation, Neoplastic; Globulins; Horses; Immunosuppression Therapy; Lung; Lung Neoplasms; Lymph Nodes; Male; Mice; Mice, Inbred Strains; Mitolactol; Neoplasm Metastasis; Neoplasm Transplantation; Nitrogen Mustard Compounds; Osteosarcoma; Propionibacterium acnes; Radiation Effects; Sarcoma, Experimental
PubMed: 1056314
DOI: 10.1002/ijc.2910150408 -
European Journal of Cancer & Clinical... Jun 19821,2-Anhydro-6-bromo-6-deoxygalactitol (BrEpG) and its D-mannitol analogue (BrEpM) intermediary metabolites in the conversion of dibromodulcitol (DBD) and dibromomannitol... (Comparative Study)
Comparative Study
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.
Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Dianhydrogalactitol; Lethal Dose 50; Leukopenia; Mannitol; Mice; Mitobronitol; Mitolactol; Rats
PubMed: 6811281
DOI: 10.1016/0277-5379(82)90227-9 -
Journal of Clinical Oncology : Official... May 1992The study was undertaken to evaluate a chemotherapy protocol against recurrent malignant gliomas that was designed to combat presumed chloroethyl-nitrosourea (NU)...
PURPOSE
The study was undertaken to evaluate a chemotherapy protocol against recurrent malignant gliomas that was designed to combat presumed chloroethyl-nitrosourea (NU) resistance.
PATIENTS AND METHODS
All patients had malignant gliomas and had failed prior therapy. Patients were stratified as having either glioblastoma multiforme (GM) or anaplastic gliomas (AG) and as having failed radiotherapy (RT) only or both RT and chemotherapy. Chemotherapy consisted of six drugs: before lomustine (CCNU), thioguanine (TG), dibromodulcitol (mitolactol; DBD), and procarbazine (PCB) were given to enhance CCNU-induced tumor-cell kill and to reduce alkyltransferase repair of ethylated DNA. A fluorouracil-hydroxyurea (FUHU) combination was given 2 weeks later to kill cells that began to cycle after the challenge of the first four drugs (TPDC-FUHU chemotherapy).
RESULTS
Of the 88 assessable patients, 37 had GM, 38 had AG, and 13 had other primary and metastatic brain tumors. For GM patients, 61% had a partial response (PR) or stable disease (SD) for a median of 9.3 months if RT only failed, and 58% had a PR or SD for a median of 5.1 months if they had previously been treated with an NU. For AG patients, 92% had a PR or SD for a median of 15 months if RT only had failed, but only 38% had a PR or SD for a median of 10.6 months if they had been previously treated with a NU. Activity was also seen against other recurrent or progressive primary and metastatic brain tumors.
CONCLUSIONS
TDPC-FUHU chemotherapy is a highly effective form of chemotherapy for both recurrent GM and AG patients. This study suggests but does not prove that this combination may be superior to other NU-based treatments for recurrent malignant glioma patients who fail RT. Because of the activity of this chemotherapy, we intend to evaluate more fully this approach in a randomized study.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Cycle; Child; Child, Preschool; Drug Resistance; Female; Fluorouracil; Glioblastoma; Glioma; Humans; Hydroxyurea; Male; Middle Aged; Neoplasm Recurrence, Local; Nitrosourea Compounds
PubMed: 1314890
DOI: 10.1200/JCO.1992.10.5.766 -
Journal of Neuro-oncology Jul 1997We performed a randomized trial to compare survival distributions and toxicity of radiation therapy (RT) and DBD with RT and BCNU in patients with high-grade astrocytoma. (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
PURPOSE
We performed a randomized trial to compare survival distributions and toxicity of radiation therapy (RT) and DBD with RT and BCNU in patients with high-grade astrocytoma.
METHODS
A total of 238 patients with supratentorial grade 3 and grade 4 astrocytoma were studied. Patients were stratified by age, extent of surgery, tumor grade, and performance score and randomly assigned to receive RT 55-60 Gy and either DBD, 200 mg/m2 orally on Days 1-10 every five weeks or BCNU, 200 mg/m2 intravenously every seven weeks. Median age was 60 years; 62% were 55 years or older. Eighty-three percent had subtotal resection, 58% had grade 4 tumors, and 83% had performance scores of 0-2.
RESULTS
Survival distributions for all patients in the two arms were similar, with median survival of 41 weeks in each arm. Time to progression distributions were virtually identical, with medians of 22 weeks. BCNU produced significantly greater hematologic toxicity; median leukocyte and platelet nadirs on the first cycle were 3.6 vs. 4.7 (P = 0.0001) and 117 vs. 162 (P < 0.0001), and overall platelet nadirs were 80.5 vs. 114 (P = 0.0019). Non-hematologic toxicities were also significantly greater with BCNU, including nausea (57% vs. 31%; P < 0.0001) and vomiting (45% vs. 17%; P < 0.0001).
CONCLUSION
This trial found no evidence of differences in treatment efficacy when either DBD or BCNU is combined with radiation therapy for patients with high-grade astrocytoma.
Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carmustine; Combined Modality Therapy; Female; Glioblastoma; Humans; Male; Middle Aged; Mitolactol; Survival Rate
PubMed: 9195495
DOI: 10.1023/a:1005735405986 -
Blood Oct 1974
Topics: Anemia; Azauridine; Blood Cell Count; Blood Platelets; Bone Marrow Examination; Busulfan; Cell Transformation, Neoplastic; Humans; Hydroxyurea; Karyotyping; Leukemia, Myeloid; Mitolactol; Nitrogen Mustard Compounds; Phenylalanine; Primary Myelofibrosis; Prognosis; Splenomegaly; Thrombocytosis
PubMed: 4528824
DOI: No ID Found -
Journal of Clinical Oncology : Official... Mar 1997To evaluate a combination of thioguanine, procarbazine, dibromodulcitol, CCNU (CCNU), fluorouracil, and hydroxyurea (TPDC-FuHu), designed to improve the efficacy of... (Clinical Trial)
Clinical Trial
PURPOSE
To evaluate a combination of thioguanine, procarbazine, dibromodulcitol, CCNU (CCNU), fluorouracil, and hydroxyurea (TPDC-FuHu), designed to improve the efficacy of CCNU, in the treatment of recurrent metastatic brain tumors.
PATIENTS AND METHODS
One hundred fifteen patients with progressive or recurrent metastatic brain tumors that failed to respond to surgery and/or radiation therapy were enrolled onto a multicenter prospective study between 1989 and 1995. Patients received TPDC-FuHu in a repeated cycle every 6 weeks until recurrence or until they completed six courses.
RESULTS
Ninety-seven patients were assessable at the end of the study. Forty-eight had lung cancer (39 non-small-cell [NSCLC] and nine small-cell [SCLC]), 28 had breast cancer, nine had melanoma, and 12 had adenocarcinoma of different origins (three colon, two kidney, one bladder, one stomach, and five of unknown origin). The response and stable disease (SD) rate (overall response rate) was 52%, 66%, 60%, and 22% in patients with NSCLC, SCLC, breast cancer, and melanoma, respectively. Median time to progression (MTP) was 12, 26, 12, and 6 weeks, respectively, for the four groups. Side effects were mild to moderate in the majority of patients. Severe myelosuppression (grade 4) occurred in only 11% of the patients.
CONCLUSION
TPDC-FuHu chemotherapy is an active treatment against recurrent brain metastases from breast cancer and SCLC, and to a lesser extent from NSCLC. This regimen is well tolerated and has acceptable toxicity.
Topics: Adenocarcinoma; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disease Progression; Female; Fluorouracil; Humans; Hydroxyurea; Lomustine; Lung Neoplasms; Male; Middle Aged; Mitolactol; Procarbazine; Prospective Studies; Thioguanine
PubMed: 9060546
DOI: 10.1200/JCO.1997.15.3.1063