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Biochemistry Jul 1986Mitomycin C (1) is a clinically used antitumor antibiotic that binds covalently to deoxyribonucleic acid under reductive or acidic catalysis. We have determined the...
Mitomycin C (1) is a clinically used antitumor antibiotic that binds covalently to deoxyribonucleic acid under reductive or acidic catalysis. We have determined the structures of the adducts resulting from attack of reductively activated 1 on the dinucleoside phosphate d(GpC) to be N2-(2'' beta, 7''-diaminomitosen-1''alpha-yl)-2'-deoxyguanosine (2) and its 1'' beta-isomer (3). This represents a revision of the previously reported structures for these adducts in that the mitomycin residue is linked to the N2- rather than O6-position of 2'-deoxyguanosine. This revision is the result of applying to the mitomycin case a newly developed general method that leads to unambiguous assignment of the linkage position in complex alkylated guanosines. The method as described here takes advantage of the resolution enhancement gained by calculation of the second derivatives of absorbance Fourier transform infrared spectra. In addition, we present 1H NMR data that corroborate the assigned structures of 2 and 3 and that should serve as a useful reference for future investigations into the binding of mitomycin C to DNA. The convenient synthesis of adducts 2 and 3 from deoxyguanosine and mitomycin C reported here should facilitate such investigations as well. Furthermore, we demonstrate a useful acetylation procedure for adducts and metabolites of mitomycin C that furnishes spectroscopically superior chemical derivatives (e.g., triacetates 4 and 5, derived from acetylation of adducts 2 and 3).
Topics: Deoxyguanosine; Fourier Analysis; Guanosine; Magnetic Resonance Spectroscopy; Mitomycin; Mitomycins; Spectrophotometry, Infrared
PubMed: 3092855
DOI: 10.1021/bi00363a024 -
Ophthalmology Mar 1989
Topics: Humans; Mitomycin; Mitomycins; Ophthalmic Solutions; Pterygium
PubMed: 2496370
DOI: 10.1016/s0161-6420(89)32901-0 -
Angewandte Chemie (International Ed. in... Aug 2014A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C, involving a novel electrophilic spiro-cyclopropane intermediate is...
A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C, involving a novel electrophilic spiro-cyclopropane intermediate is hypothesized. Rational design and substantial structural simplification permitted the expedient chemical synthesis and rapid discovery of MTSB-6, a mitomycin C analogue which is twice as potent as mitomycin C against the prostate cancer cells. MTSB-6 shows improvements in its selective action against noncancer prostate cells over mitomycin C. This hypothesis-driven discovery opens novel yet synthetically accessible mitosene structural space for discovering more potent and less toxic therapeutic candidates.
Topics: Cell Line; Cell Survival; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Mitomycin; Mitomycins; Molecular Structure; Structure-Activity Relationship
PubMed: 25044229
DOI: 10.1002/anie.201402268 -
Environmental and Molecular Mutagenesis 1987Mouse and Chinese hamster models have been extensively used for assessing the cytogenetic effects of environmental carcinogens and mutagens. However, there is little... (Comparative Study)
Comparative Study
Mouse and Chinese hamster models have been extensively used for assessing the cytogenetic effects of environmental carcinogens and mutagens. However, there is little information on comparative analysis of chromosomal damage in these species under in vivo and in vivo/in vitro (culturing of cells from animals exposed to the test compound) systems. To obtain such information, mice and Chinese hamsters were injected with varying concentrations (0.5-6.0 mg/kg) of mitomycin C, an antineoplastic drug. The bone marrow and spleen cells were analyzed for the number of sister chromatid exchanges (SCEs) under in vivo and in vivo/in vitro conditions. The results indicated a dose-related SCE response that varied with species, tissues, and assay conditions. The mouse cells appeared more sensitive to the effects of mitomycin C than did Chinese hamster cells. In general, the SCE frequencies were relatively higher under in vivo conditions than under in vivo/in vitro conditions in both species. The spleen cells had higher SCE values than bone marrow cells under in vivo/in vitro conditions in both species. These differences may be related to the pharmacokinetic properties of the drug in different species and tissues, to treatment conditions, or to the repair capabilities of the cells. This study also indicates the usefulness of recently established bone marrow and spleen in vivo/in vitro cell cultures for comparative cytogenetic analysis.
Topics: Animals; Bone Marrow; Cells, Cultured; Cricetinae; Cricetulus; Male; Mice; Mitomycin; Mitomycins; Mutagenicity Tests; Organ Specificity; Sister Chromatid Exchange; Species Specificity; Spleen
PubMed: 3121309
DOI: 10.1002/em.2850100206 -
Cancer Research Oct 1983This paper describes an investigation into the pharmacokinetic behavior of mitomycin C (MMC) in 36 patients receiving either single-agent chemotherapy (10 to 20 mg/sq...
This paper describes an investigation into the pharmacokinetic behavior of mitomycin C (MMC) in 36 patients receiving either single-agent chemotherapy (10 to 20 mg/sq m), or a combination regimen including MMC (5 to 10 mg/sq m). A high-performance liquid chromatographic assay of MMC was applied for the analysis of plasma, urine, bile, and ascites fluid samples. The detection limit is 1 ng/ml sample. Most patients were given short-term i.v. infusion, although other methods of administration were used as well. Most plasma concentration-time curves fit a two-compartment model. Pharmacokinetic parameters revealed large interindividual variations. Median terminal half-lives in single-agent chemotherapy and combination chemotherapy were 50 and 42 min, respectively. The apparent volume of the central compartment was 7 liters/sq m in both groups. The volume of distribution was 22 liters/sq m in single-agent chemotherapy, and 25 litres/sq m in combination chemotherapy. Linear regression analysis of the area under the plasma concentration-time curve versus the dose did not produce any evidence that the pharmacokinetics was dose dependent. However, differences were observed between patients receiving MMC alone and those on combination chemotherapy, in particular with regard to the total body clearance: 18 liters/hr/sq m for single-agent chemotherapy and 28 liters/hr/sq m for combination chemotherapy. Urinary recovery was limited to a maximum of 15% of the administered dose. In one patient studied, MMC was found to be present in the bile. There is evidence for enterohepatic circulation of MMC, and MMC was also found to penetrate into the ascites fluid.
Topics: Adult; Aged; Antibiotics, Antineoplastic; Ascitic Fluid; Bile; Chromatography, High Pressure Liquid; Female; Half-Life; Humans; Kinetics; Male; Middle Aged; Mitomycin; Mitomycins; Neoplasms
PubMed: 6411336
DOI: No ID Found -
Biochemistry Mar 1990An extensive series of oligodeoxyribonucleotides was reacted with reductively activated mitomycin C (MC), and the resulting cross-linked drug-oligonucleotide complexes...
An extensive series of oligodeoxyribonucleotides was reacted with reductively activated mitomycin C (MC), and the resulting cross-linked drug-oligonucleotide complexes were isolated by reverse-phase HPLC and characterized by nucleoside and MC-nucleoside adduct analysis. HPLC also served for assay of the yield of cross-linked oligonucleotides. AT-rich duplex oligonucleotides, containing a single central CG.CG, gave high yields of cross-links between the two guanines while those having GC.GC, instead, gave none. In another series, the central sequences CGC.GCG and CGC.ICG both yielded 50% cross-link while CGC.GCI was completely resistant. Cross-linking was conducted also in two steps: Oligonucleotides substituted monofunctionally by MC at guanine at either a CG or GC sequence were annealed with their complementary strands followed by reductive reactivation of the bound MC to form a cross-link. The CG oligomers were cross-linked quantitatively while the GC ones were again resistant. These results show unambiguously that the MC cross-link is absolutely specific to the CG.CG duplex sequence, confirming our previous finding [Chawla, A.K., Lipman, R., & Tomasz, M. (1987) in Structure and Expression, Volume 2: DNA and Its Drug Complexes (Sarma, R.H., & Sarma, M.H., Eds.) Adenine Press, Guilderland, NY]. Evidence is presented that this specificity is due to the specific orientation of the monofunctionally attached MC in the minor groove. Superimposed on the CG.CG requirement, a four-base-pair sequence preference was observed at PuCGPyr.PuCGPyr sequences. This suggests that the guanine N2 atom of GpPyr is more reactive toward the drug than that of GpPu, due to the favorable effect of the negative dipole of the O2 of the Pyr on the reaction; in accordance, GpT was more reactive than GpC.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Base Sequence; Chromatography, High Pressure Liquid; Cross-Linking Reagents; DNA; Mitomycin; Mitomycins; Molecular Sequence Data; Nucleic Acid Conformation; Oligodeoxyribonucleotides
PubMed: 2110821
DOI: 10.1021/bi00464a016 -
Journal of Chromatography May 1983A method is given for the determination of the antineoplastic drug mitomycin C in plasma and urine samples. Mitomycin is isolated from the biological matrix with the aid...
A method is given for the determination of the antineoplastic drug mitomycin C in plasma and urine samples. Mitomycin is isolated from the biological matrix with the aid of a Sep-Pak C18 extraction column and eluted with methanol. The methanol is evaporated and the residue is redissolved in the chromatographic mobile phase (methanolic phosphate buffer). Mitomycin C is separated from coextracted compounds by reversed-phase liquid chromatography on a LiChrosorb RP-8 column. A high detection sensitivity and selectivity was obtained by photometric measurements at 365 nm. The precision of the determinations was better than 6% relative standard deviation for plasma samples within the range 2-1000 ng/ml, and for urine samples within the range 0.5-4.4 micrograms/ml. The pH-dependent stability of mitomycin in buffer solutions has been studied.
Topics: Buffers; Chromatography, Liquid; Half-Life; Humans; Kinetics; Mitomycin; Mitomycins; Spectrophotometry; Temperature
PubMed: 6409914
DOI: 10.1016/s0378-4347(00)84429-1 -
The Journal of Antibiotics Jul 1956
Topics: Anti-Bacterial Agents; Antineoplastic Agents; Humans; Mitomycin; Mitomycins; Streptomyces
PubMed: 13385186
DOI: No ID Found -
Journal of Neurosurgery. Spine Sep 2008In this prospective, randomized clinical study the authors sought to evaluate the effects of locally applied mitomycin C on peridural fibrosis during lumbar... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECT
In this prospective, randomized clinical study the authors sought to evaluate the effects of locally applied mitomycin C on peridural fibrosis during lumbar microdiscectomy.
METHODS
Patients undergoing lumbar disc surgery were randomly divided into 2 groups. Thirty patients had 1 mg/ml mitomycin C applied at the site of discectomy for 5 minutes, and 30 age- and sex-matched patients underwent lumbar microdiscectomy without mitomycin C application as the control group. The groups were compared for degree of postoperative neurological function, radicular/back pain, and degree of peridural fibrosis on MR imaging 6 months after the operation.
RESULTS
The median follow-up was 18 months. No serious drug adverse effects and no clinically significant laboratory adverse effects were reported in patients in the mitomycin C group. Patients in both groups showed similar clinical recoveries postoperatively. On postoperative evaluation of the MR images, pain scores, and neurological function, patients given mitomycin C have shown no reduction of peridural fibrosis either clinically or radiographically.
CONCLUSIONS
Mitomycin C is easy to use and safe in patients undergoing lumbar microdiscectomy. However, no benefit was observed either clinically or radiographically in this study.
Topics: Adult; Diskectomy; Dura Mater; Female; Fibrosis; Follow-Up Studies; Humans; Lumbar Vertebrae; Magnetic Resonance Imaging; Male; Mitomycin; Postoperative Complications
PubMed: 18928218
DOI: 10.3171/SPI/2008/9/9/243 -
Journal of Pharmaceutical Sciences Sep 1984A normal-phase high-performance liquid chromatographic (HPLC) assay was developed for the determination of mitomycin C in plasma and urine. The method involves...
A normal-phase high-performance liquid chromatographic (HPLC) assay was developed for the determination of mitomycin C in plasma and urine. The method involves extraction of mitomycin C from plasma or urine into ethyl acetate-2-propanol-chloroform (70:15:15) with UV detection at 365 nm. Quantitation was performed with an internal standard (porfiromycin) by the peak height ratio method. Excellent correlation was obtained between the HPLC assay and the established microbiological cup-plate bioassay. The pharmacokinetics of mitomycin C were investigated in beagle dogs following a 1-mg/kg iv (22-mg/m2) bolus dose. The plasma mitomycin C concentration versus time data were analyzed by using an open three-compartment model. The average volume of distribution was 1.90 L or 17% of body weight for the central compartment and 7.7 L or 68% of body weight for the terminal elimination phase. The volumes of distribution at steady state, calculated by model-dependent and -independent methods, compared very well with each other and were 6.5 L or 58% of body weight. Total body clearance averaged 112 mL/min, and the mean terminal plasma half-life was 53 min. The 0-24-h urinary excretion of intact mitomycin C accounted for 19% of the dose. The terminal half-life and percent urinary recovery of mitomycin C in dogs is similar to that in humans. Based on these observations, the dog appears to be a good model for studying the disposition of mitomycin C.
Topics: Animals; Chromatography, High Pressure Liquid; Dogs; Female; Injections, Intravenous; Kinetics; Mitomycin; Mitomycins
PubMed: 6436466
DOI: 10.1002/jps.2600730909