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Journal of the National Cancer Institute May 1977The pharmacokinetics of dianhydrogalactitol (DAG), NSC-132313, were studied in the beagle dog at doses of 3 mg - kg-1 and 6 mg - kg-1. DAG concentrations in plasma were...
The pharmacokinetics of dianhydrogalactitol (DAG), NSC-132313, were studied in the beagle dog at doses of 3 mg - kg-1 and 6 mg - kg-1. DAG concentrations in plasma were determined by a gas chromatographic method capable of specifically detecting the parent drug and differentiating between it and products of its degradation or metabolism. Plasma disappearance time curves were generated and shown to follow simple two-compartment model behavior after iv administration of DAG. Distribution and elimination of DAG appeared to be dose-independent in the limited dose range studied. After iv administration, the drug was rapidly distributed throughout extracellular fluids (volume of the central compartment = 462 ml - kg-1) and subsequently was rapidly cleared (total body clearance = 23.4 ml - min-1 - kg-1) and eliminated (t1/2, b = 26.2 min) from the animal. Experiments (in vitro) with the use of radiolabeled DAG indicated that the drug binds reversibly and irreversibly to red blood cells.
Topics: Animals; Antineoplastic Agents; Chromatography, Gas; Dogs; Erythrocytes; Ethers, Cyclic; Female; Galactitol; Male; Metabolic Clearance Rate; Sugar Alcohols
PubMed: 857026
DOI: 10.1093/jnci/58.5.1311 -
Carbohydrate Research Jun 1977alpha, omega-Disubstituted derivatives of 2,3-anhydro-DL-threitol (2), 2,3-anhydroerythritol (4), 2,3:4,5-dianhydrogalactitol (8), and 2,3:4,5-dianhydroallitol (12) have...
alpha, omega-Disubstituted derivatives of 2,3-anhydro-DL-threitol (2), 2,3-anhydroerythritol (4), 2,3:4,5-dianhydrogalactitol (8), and 2,3:4,5-dianhydroallitol (12) have been synthesised by epoxidation of the appropriate alkeness and dienes. Benzyloxy carbonyl groups were used for protecting the primary hydroxyl groups during epoxidation.
Topics: Alkylating Agents; Erythritol; Ethers, Cyclic; Galactitol; Magnetic Resonance Spectroscopy; Methods; Structure-Activity Relationship; Sugar Alcohols
PubMed: 880588
DOI: 10.1016/s0008-6215(00)84235-4 -
Cancer Treatment Reports Aug 1977The distribution of iv administered 3H-dianhydrogalactitol (DAG) in the plasma, cerebrospinal fluid (CSF), brain, and tumor tissue was studied in 11 patients. DAG...
The distribution of iv administered 3H-dianhydrogalactitol (DAG) in the plasma, cerebrospinal fluid (CSF), brain, and tumor tissue was studied in 11 patients. DAG entered the CSF and was slowly eliminated, with a half-life of 20 hours. Unchanged DAG accounted for about 6%-30% of the total radioactivity in the CSF. All the tumors accumulated the drug to a higher extent than the intact white matter, except the one meningioma studied. The highest uptake was observed in the relatively benign astrocytic tumors.
Topics: Adult; Brain; Ethers, Cyclic; Galactitol; Glioma; Half-Life; Humans; Middle Aged; Nerve Tissue; Sugar Alcohols; Time Factors
PubMed: 890693
DOI: No ID Found -
Cancer Treatment Reports Jul 1976Dianhydrogalactitol was given to 28 patients with a variety of advanced solid tumors on a weekly schedule in iv doses ranging from 2 to 80 mg/m2. No significant toxicity... (Clinical Trial)
Clinical Trial
Dianhydrogalactitol was given to 28 patients with a variety of advanced solid tumors on a weekly schedule in iv doses ranging from 2 to 80 mg/m2. No significant toxicity was encountered at doses up to 40 mg/m2/week for 4 weeks. At higher doses mild-to-moderate nausea and vomiting and hematologic toxicity were noted. Thrombocytopenia was more common than granulocytopenia and frequently resolved more slowly. No adverse drug-realted effects on liver, renal, coagulation, or cardiac function were seen. Although no patient had significant antitumor response (as strictly defined), objective improvement was noted in two patients, one with hypernephroma and the other with malignant melanoma. for phase II studies, a weekly dose of 70 mg/m2 is recommended for patients with normal hematopoiesis, with reduction by 25% (55 mg/m2) in patients with extensive prior radiation therapy, prior chemotherapy, and/or widespread metastasis to the bone.
Topics: Adult; Aged; Agranulocytosis; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Ethers, Cyclic; Female; Galactitol; Humans; Injections, Intravenous; Male; Middle Aged; Sugar Alcohols; Thrombocytopenia
PubMed: 795538
DOI: No ID Found -
Cancer Treatment Reports Sep 1976Phase II chemotherapy trials of dianhydrogalactitol and VP-16-213 were conducted in patients with metastatic colorectal cancer who had measurable malignant disease which... (Clinical Trial)
Clinical Trial
Phase II chemotherapy trials of dianhydrogalactitol and VP-16-213 were conducted in patients with metastatic colorectal cancer who had measurable malignant disease which served as indicators of response to therapy. Dianhydrogalactitol was given in a 5-day course at a dosage of 30 mg/m2/day. Toxic reactions included nausea, vomiting, leukopenia, thrombocytopenia, and anemia. There was a definite tendency to a compounding of hematologic toxicity with repeated courses. No evidence of objective therapeutic response was observed among 30 patients treated. VP-16-213 was given at a dosage of 130 mg/m2 on Days 1, 3, and 5. Toxic reactions included nausea, vomiting, alopecia, leukopenia, thrombocytopenia, and anemia. Hematologic toxicity was more severe in patients with elevated serum bilirubin levels. No evidence of objective therapeutic response was observed among 28 patients treated.
Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Clinical Trials as Topic; Colonic Neoplasms; Drug Evaluation; Ethers, Cyclic; Etoposide; Female; Galactitol; Humans; Male; Middle Aged; Podophyllotoxin; Rectal Neoplasms; Sugar Alcohols
PubMed: 797447
DOI: No ID Found -
Chemico-biological Interactions May 1981In vivo alkylation of Yoshida sarcoma cell DNA by 3H-labelled 1,2:5,6-dianhydrogalactitol (DAG) yielded N-7 monogalactitylguanines and 1,6-di-(guanin-7-yl)-galactitol,...
In vivo alkylation of Yoshida sarcoma cell DNA by 3H-labelled 1,2:5,6-dianhydrogalactitol (DAG) yielded N-7 monogalactitylguanines and 1,6-di-(guanin-7-yl)-galactitol, similar to the alkylated products obtained by in vitro reaction of DNA with dianhydrogalactitol in neutral solution. The ratio between monoalkylguanines and diguaninyl product was 2-2.5, slightly increasing with doses. Persistence of alkylated products in DNA was followed in function of time. There was no significant loss of either monoalkylated bases or diguaninyl derivative during the observation period i.e. 7-24 h after treatment. In contrast, the physical measurements of the amount of renaturable DNA showed a rapid opening of cross-links in the same period. Taking the presence of diguaninyl moiety as an indicator of cross-links in DNA, these two latter findings show an apparent contradiction which could be reconciled however by the mechanism proposed by Reid and Walker (Biochim. Biophys. Acta, 179 (1969) 179) for the removal of cross-linkage induced by HN2. Accordingly, one arm of the cross-links is removed, probably enzymically, leaving the DNA non-renaturable, while the other arm of cross-link is still covalently attached to the DNA molecule rendering possible the detection of diguaninyl moiety in DNA at some later time. This concept for the removal of cross-links from DNA seems to be supported by our results too.
Topics: Alkylating Agents; Animals; Binding Sites; Cross-Linking Reagents; DNA; DNA, Neoplasm; Dianhydrogalactitol; Rats; Sarcoma, Yoshida; Sugar Alcohols
PubMed: 7214602
DOI: 10.1016/0009-2797(81)90144-7 -
Antibiotics and Chemotherapy 1978Alkylating anticancer drugs are varied in chemical structure, alkylating moieties, and likely mechanisms of cytotoxic activity for vital normal cells and sensitive tumor... (Review)
Review
Alkylating anticancer drugs are varied in chemical structure, alkylating moieties, and likely mechanisms of cytotoxic activity for vital normal cells and sensitive tumor cells. This has been objectively documented by numerous examples illustrating: (1) different in vitro and in vivo reaction products; (2) greater than additive, additive, and less than additive cytotoxicity of drug combinations for vital normal cells in the mouse; (3) readily reproducible and often marked therapeutic synergism between a variety of 2-drug combinations of alkylating agents against a wide variety of histologic types of murine tumors, and (4) observed resistance and cross-resistance of a variety of murine tumors, selected for resistance to specific alkylating agents, compatible with recognized chemical and functional differences between these drugs. The most important observations on resistance and cross-resistance reported are: (a) L1210 cells selected for complete resistance to cyclophosphamide (CPA) retain full sensitivity to selected nitrosoureas (BCNU, CCNU, MeCCNU), chlorozotocin), dianhydrogalactitol, and cis-DDPt, while retaining marked but somewhat reduced sensitivity to L-PAM, piperazinedione, and thioTEPA. (B) L1210 cells selected for resistance to BCNU retain full sensitivity to CPA, L-PAM, and dianhydrogalactitol. They show complete cross-resistance to BIC and variable cross-resistance to other selected nitrosoureas and piperazinedione. (c) L1210/L-PAM has incomplete but marked resistance to L-PAM. It is similar to the parent drug-sensitive line (L1210/0) in response to BCNU, CCNU, MeCCNU, and BIC. It is variably (usually moderately) cross-resistant to CPA, chlorozotocin, dianhydrogalactitol, and thioTEPA, but is completely cross-resistant to cis-DDPt. These resistance and cross-resistance patterns, which are consistent with most other biological and chemical principles established with these alkylating agents, may be useful in selecting alkylating drug combinations for inclusion in chemotherapy protocols in man which, on the basis of diverse observations in animal tumor systems, appear to be clearly indicated.
Topics: Alkylating Agents; Animals; Carmustine; Cell Survival; Cyclophosphamide; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Leukemia L1210; Melphalan; Mice; Neoplasms, Experimental
PubMed: 348078
DOI: 10.1159/000401484 -
Cancer Treatment Reports Oct 1976Thirty dogs in four different treatment schedules and 14 monkeys in a single multiple-treatment schedule were used to evaluate the toxicity of dianhydrogalactitol....
Thirty dogs in four different treatment schedules and 14 monkeys in a single multiple-treatment schedule were used to evaluate the toxicity of dianhydrogalactitol. Highest nontoxic, low toxic, high toxic, and lethal doses were established in single injection doses and five daily injections in dogs, and in five daily injections in monkeys. Dose ranges of 20-320 mg/m2 (single injection) and 5-80 mg/m2 (five daily injections) in dogs, and 3-96 mg/m2 (five daily injections) in monkeys were established. The monkeys were more sensitive than dogs to the low toxic dose and more tolerant to the high toxic dose in the repeated daily injections. The dose-response curves for the dogs and monkeys had similar slopes and inflection points. Because of the steep slope between the lethal dose and the highest nontoxic dose in both species, caution should be used in the initial clinical trials.
Topics: Animals; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Ethers, Cyclic; Female; Galactitol; Haplorhini; Lethal Dose 50; Macaca mulatta; Male; Sugar Alcohols
PubMed: 828520
DOI: No ID Found -
Cancer Treatment Reports Apr 1979Dianhydrogalactitol given iv in a schedule of 30 mg/m2/day for 5 consecutive days every 4 weeks was administered to 27 patients with metastatic malignant melanoma. All...
Dianhydrogalactitol given iv in a schedule of 30 mg/m2/day for 5 consecutive days every 4 weeks was administered to 27 patients with metastatic malignant melanoma. All patients had received extensive prior therapy including chemotherapy and had progressive disease at the start of the study. Of 24 patients evaluable for response, 21 demonstrated progressive disease and three had stable disease for periods of from 4 to 11 months. No objective responses were observed. Two of the remaining three patients died 6 and 10 days after entry in the study, while the third refused to return after one drug course. Adverse effects included myelosuppression in eight patients, nausea and vomiting in five patients, and alopecia in one patient. Dianhydrogalactitol is considered to be insignificantly active in the secondary treatment of metastatic malignant melanoma at the dose and schedule studied.
Topics: Adult; Aged; Bone Marrow; Dianhydrogalactitol; Digestive System; Drug Evaluation; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Sugar Alcohols
PubMed: 445506
DOI: No ID Found -
Cancer Treatment Reports Aug 1982
Topics: Adult; Aged; Astrocytoma; Brain Neoplasms; Carmustine; Dianhydrogalactitol; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Oligodendroglioma; Prognosis; Sugar Alcohols
PubMed: 7105055
DOI: No ID Found