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At least 19 recordsLinked to original sources
PubMed1985

Effects of Tau and MAP2 on the interaction of maytansine with tubulin: inhibitory effect of maytansine on vinblastine-induced aggregation of tubulin.

Maytansine, a potent inhibitor of mitosis and in vitro microtubule assembly, was used to demonstrate a striking difference in the mechanism by which two of the main groups of brain microtubule-associated proteins, Tau and MAP2, interact with tubulin. At the low concentrations of 0.5 to 2 microM, maytansine inhibited Tau-catalyzed tubulin assembly more effectively than it did MAP2-catalyzed assembly. This effect differed markedly from that of vinblastine, although both drugs bind competitively to tubulin. At the same low concentrations, vinblastine almost completely inhibited Tau- and MAP2-mediated tubulin assembly. At higher concentrations of 10 to 40 microM, a more striking difference was observed between the actions of the two drugs. Maytansine very effectively inhibited tubulin assembly promoted by either Tau or MAP2. Vinblastine also had this effect on MAP2-mediated tubulin assembly but in the presence of Tau induced extensive tubulin aggregation into spirals. In addition maytansine strongly inhibited vinblastine-induced Tau-dependent tubulin aggregation into spiral polymers. Even at very low concentrations, maytansine completely inhibited the effect of very high concentrations of vinblastine. These results very strongly suggest that the binding sites of maytansine and vinblastine on the tubulin molecule overlap and that the changes that they probably induce in the conformation of this molecule are markedly different, at least in the presence of microtubule-associated proteins.

Animals↗
PubMed1981

Binding of maytansine to tubulin: competition with other mitotic inhibitors.

The effect of maytansine on the binding of [3H]vinblastine and [3H]colchicine to tubulin was examined by Sephadex gel filtration column chromatography. When varying concentrations of maytansine were employed, competition between vinblastine and maytansine was observed at a vinblastine to maytansine ratio of 1:10 and 1:100, while a colchicine to maytansine ratio of 1:100 did not affect the binding of colchicine to tubulin. These results confirm earlier findings with a DEAE-cellulose disc paper assay and a tubulin polymerization assay that maytansine shares a common binding site with vinblastine and support the view that tubulin has at least two drug binding sites.

Animals↗
PubMed1978

Maytansine action on fast axoplasmic transport and the ultrastructure of vagal axons.

Maytansine, an ansa macrolide now in clinical trials as an antineoplastic drug, is a potent inhibitor of microtubule polymerization. Since microtubules are involved in axoplasmic transport, the effect of maytansine on transport was examined. Fast axoplasmic transport of proteins and the axonal ultrastructure was studied in the vagus nerve of cats exposed in vitro to maytansine. Tritiated leucine was microinjected into the nodose ganglion; after 2 hr for incorporation into proteins, nerves were dissected out for transport and ultrastructural studies and incubated for 2.5 hr in Krebs-Ringer solution with 100, 20, 10, 5, or 1 micron maytansine. A reduction in the number of microtubules and a partial blockage of fast axoplasmic transport was observed at 20 and 100 micron maytansine; at 10 micron no detectable changes were observed. These findings show that maytansine in vitro induces alterations of the neurofibrillar elements concomitant with a partial blockage of fast axoplasmic transport.

Animals↗
PubMed1978

Teratogenic and cytogenetic effects of some plant-derived antitumor agents (vincristine, colchicine, maytansine, VP-16-213 and VM-26) in mice.

The teratogenic effects of three new plant-derived antitumor agents, maytansine, VP-16-213 and VM-26, were compared to the effects of vincristine and colchicine in pregnant Swiss albino mice that received a single ip injection of drug on day 6, 7 or 8 of gestation. Cytogenetic studies were also performed using maternal bone marrow and embryos obtained 48 hours after injection of maytansine, vincristine, VP-16-213, VM-26 and colchicine on day 6, 7 or 8 of gestation. A close correlation between teratogenic and cytogenetic effects was not noted among the compounds tested. Vincristine had greater embryotoxic and teratogenic activity than maytansine at equimolar doses (0.36 mu moles/kg), with the peak effects appearing after injection on day 7 of gestation. Colchicine, VP-16-213 and VM-26 were comparatively less potent than maytansine and vincristine, since doses of 2.5 mu moles/kg (colchicine and VP-16-213) and 1.5 mu moles/kg (VM-26) were required to elicit embryotoxic effects. At their teratogenic doses, all compounds induced various cranial abnormalities including exencephaly, hydrocephalus, anophthalmia and microtia, as well as major skeletal malformations. The teratogenic dose of vincristine is comparable to its effective antitumor dose in transplantable rodent tumor systems; in contrast, the teratogenic dose of maytansine in approximately 10-fold higher than its antitumor dose. Of the compounds studied, VP-16-213 and VM-26 exerted the most consistent cytogenetic effects in embryonic tissue. Alarge proportion of the structural chromosome aberrations induced in embryonic cells by VM-26 were stable and are most likely capable of surviving at least one cell division.

Abnormalities, Drug-Induced↗
PubMed1979

Cell cycle phase-specific cytotoxicity of the antitumor agent maytansine.

The objective of this investigation was to study the effects of maytansine on the cell cycle kinetics of HeLa cells. The results of this study indicate that maytansine is a very potent mitotic inhibitor and that it has no effect on macromolecular synthesis. Maytansine-induced cytotoxicity was dependent upon the position of the cell in the cell cycle. Mitotic and G2 cells are most sensitive to this agent, while G1 phase cells are the most resistant, with S-phase cells being intermediate. Small (0.82 X 10(-8) M) fractionated doses given at an interval of 8 hr have been found to be more cytotoxic than was a large (1.63 X 10(-8) M) single dose. In evaluating the drug combinations, we observed that the schedule in which 1-beta-D-arabinofuranosylcytosine treatment was followed by maytansine treatment exhibited greater cell kill than the reverse sequence. No schedule-dependent effects were observed when maytansine was tried in combination with Adriamycin.

Cell Cycle↗
PubMed1985

Maytansine inhibits nucleotide binding at the exchangeable site of tubulin.

The antineoplastic drug maytansine inhibits the binding of exogenously added radiolabeled GDP and GTP to tubulin (50% inhibition at 9-10 microM drug at 0 degrees). Vinblastine was 1/10-th as inhibitory. Neither maytansine nor vinblastine displaced GDP from tubulin, and both drugs virtually eliminated dissociation of radiolabeled GDP from the exchangeable site. Maytansine also inhibits binding of nucleotides to a vacant exchangeable site. Maytansine thus prevents nucleotide exit and entry at the exchangeable site because of a direct physical obstruction or a conformational change in the tubulin molecule.

Binding Sites↗
PubMed1987

Rhizoxin binding to tubulin at the maytansine-binding site.

The binding of rhizoxin, a potent inhibitor of mitosis and in vitro microtubule assembly, to porcine brain tubulin was studied. Tubulin possesses one binding site for rhizoxin per molecule with a dissociation constant (Kd) of 1.7.10(-7) M. Ansamitocin P-3, a homologue of maytansine, was a competitive inhibitor of rhizoxin binding, with an inhibition constant of 1.3.10(-7) M. Vinblastine also inhibited rhizoxin binding, but was not fully competitive, and the inhibition constant was 2.9.10(-6) M. In contrast, both rhizoxin and ansamitocin P-3 were potent inhibitors of vinblastine binding. Rhizoxin inhibited tau-promoted tubulin assembly, but it, differing from vinblastine, did not induce tubulin aggregation into spirals, even at a concentration as high as 2.10(-5) M. In addition, rhizoxin strongly inhibited vinblastine-induced tau-dependent tubulin aggregation. Rhizoxin binding to tubulin was completely independent from colchicine binding. These effects resemble those of maytansine. The results suggested that rhizoxin binds to the maytansine-binding site and that the binding sites of rhizoxin and vinblastine are not the same.

Animals↗
PubMed1978

Flow microfluorometric analysis of P388 murine leukemia after administration of vincristine and maytansine in vivo.

Maytansine is a new drug undergoing clinical investigation. It has functional similarities to vincristine. Maytansine and vincristine were given to CDF1 mice with P388 leukemic ascites, and the cytokinetic response of the tumor cells was analyzed with a flow microfluorometer; mithramycin was used as the DNA fluorochrome. The results indicated a similar series of cytokinetic effects after administration of both drugs, though these effects were greater and more persistent after maytansine was given. Although both drugs produced some degree of multinucleation and endoreduplication, vincristine produced a discrete population of cells with a DNA content (fluorescence) equivalent to octoploidy (8C). Microscopy of the sorted 8C cells at 24 hours indicated 54% multinucleation and 33% mitotic figures. Most cells remained blocked in the G1-phase for at least 96 hours after administration of both drugs, which indicated that rapid DNA content distributions can be used to determine not only the effects of drugs on cell cycle distribution but also the duration of drug action.

Animals↗
PubMed1979

Pleiotropic phenotype of cultured murine cells resistant to maytansine, vincristine, colchicine, and adriamycin.

A noncloned subline of 3T3FL cells was developed that was resistant to the toxicity of the ansamycin alkaloid maytansine. Culture of 3T3FL cells with serially increasing concentrations of maytansine resulted in a cell line resistant to maytansine at concentrations 118-fold higher than concentrations cytotoxic for parental cells. Resistant cells (3T3r) exhibited cross-resistance to colchicine, vincristine, adriamycin, and, to a lesser extent, cytochalasin B. Studies of binding and uptake of tritiated colchicine suggested that drug resistance of 3T3r cells might reflect decreased uptake of drug without decreased binding to surface receptors. Murine sarcoma virus transformed 3T3r cells less efficiently than 3T3FL cells.

Animals↗
PubMed1985

Phase II trials of maytansine, low-dose chlorozotocin, and high-dose chlorozotocin as single agents against advanced measurable adenocarcinoma of the pancreas. Gastrointestinal Tumor Study Group.

One hundred and five patients with advanced measurable pancreatic carcinoma were randomized to receive therapy with maytansine, low-dose chlorozotocin (120 mg/m2), or high-dose chlorozotocin (175 mg/m2). Objective response rates were as follows: maytansine, no responses among 48 patients; low-dose chlorozotocin, none among 27; and high-dose chlorozotocin, three among 30 (10%). Among patients with excellent performance status (Eastern Cooperative Oncology Group grade of 0-1) and no prior chemotherapy, response rates were as follows: maytansine, no responses among 17 patients; low-dose chlorozotocin, none among 14; and high-dose chlorozotocin, three among 28 (11%). The responses observed with high-dose chlorozotocin were transient (5-8 weeks) and were of no benefit to the patients. None of these agents given by the methods of this study can be recommended for patients with advanced pancreatic cancer.

Adenocarcinoma↗
PubMed1978

Maytansine: a phase I study of an ansa macrolide with antitumor activity.

Maytansine has significant antitumor activity in animal model systems. The initial clinical trial of maytansine was carried out in 38 adult solid tumor patients. Five daily bolus injections were repeated at 21-day intervals. A total of 78 courses were administered over a dose range of 0.1--0.8 mg/m2/day X 5 days. Gastrointestinal toxicity was dose-related and dose-limiting at doses of greater than or equal to 0.5 mg/m2. Dose-related neurotoxicity was also observed. No drug-related myelosuppression or change in serum creatinine level was seen. Hepatic toxicity was subclinical and reversible. Of 16 patients evaluable for response, two with breast cancer had therapeutic benefit. Phase II studies of maytansine are recommended at a starting dose of 2.0--2.5 mg/m2/course repeated at 21-day intervals.

Adult↗
PubMed1977

Acute toxicity of maytansine in F344 rats.

The toxicity of maytansine given by sc administration was studied in 5-week-old mald F344 rats. The LD50 (14-day) was 0.48 mg/kg. A dose response to drug administration was indicated by body weight changes and diarrhea. A single, acutely toxic dose of maytansine was shown to possess marked activity against dividing cells which was regarded as an important factor in the pathogenesis of acute lesions in tissues with a normal high rate of cell division. Histologically, mitotic figues were observed in many tissues from 6 to 24 hours after drug administration. Subsequently, necrotizing lesions led to atrophic changes in gastrointestinal tract mucosa, thymus, spleen, bone marrow, and testis. Maytansine also induced hemorrhagic lesions in parenchymatous organs and brain and perivascular monomuclear infiltration in the meninges, and chromatolysis and vacuolation of dorsal root ganglion cells, accompanied by clinical signs of ataxia. Ulcerative skin lesions were observed at the sc site of drug administration.

Acute Disease↗
PubMed1982

Phase II study of cisplatin, maytansine, and chlorozotocin in small cell lung carcinoma (EST 2578).

Seventy-three patients with small cell lung carcinoma refractory to standard chemotherapy were entered in this phase II randomized study of cisplatin, maytansine, and chlorozotocin. Of the 58 evaluable patients, only one partial response was observed among 21 patients given cisplatin, and no responses were seen among 19 given maytansine or 18 given chlorozotocin. One patient treated with chlorozotocin and two treated with cisplatin experienced life-threatening thrombocytopenia. One third of the maytansine-treated patients experienced moderate or severe neurologic toxicity. The overall median survival was 9.7 weeks. Chlorozotocin treatment was associated with inferior survival (7.7 weeks).

Antineoplastic Agents↗
PubMedDate not supplied

Minimal single-agent activity of maytansine in refractory breast cancer: a Southwest Oncology Group study.

Maytansine is an experimental antitumor agent that has shown minimal efficacy against breast cancer with minimal myelosuppression in phase I trials. Forty-one patients with advanced drug-resistant breast cancer were treated with a 5-day intermittent iv infusion of maytansine repeated every 21 days. All patients had been heavily pretreated with cyclophosphamide, methotrexate, 5-fluorouracil, or doxorubicin, and 12 had received vinblastine, mitomycin C, or investigational drugs. All patients had measurable disease and an expected survival of 6 weeks. The average performance status was 2.5. Twelve patients did not complete one full cycle of therapy, leaving 29 evaluable for response. One patient had a partial regression of pulmonary disease, seven had transient responses of less than 50% reduction in tumor or stable disease, and 21 had progressive disease. Toxic effects (vomiting, diarrhea, ileus, lethargy, and altered mentation) were considerable. Since maytansine is a relatively nonmyelotoxic metaphase inhibitor, we feel that even minimal efficacy in heavily pretreated patients justifies further evaluation of the agent in combination therapy.

Breast Neoplasms↗
PubMedDate not supplied

Phase II study of maytansine in patients with advanced lymphomas: an Eastern Cooperative Oncology Group pilot study.

During phase I trials with maytansine some activity against lymphoma and lymphocytic leukemia was noted. Therefore, a phase II trial of maytansine in patients with advanced lymphomas refractory to conventional chemotherapy was begun. There were three partial responders (10%) among 31 patients entered in the trial. Toxicity was acceptable; gastrointestinal and neurologic side effects were the most common. Little myelotoxicity and no hepatotoxicity were observed. We conclude that maytansine has very limited activity in heavily pretreated patients with Hodgkin's disease and non-Hodgkin's lymphomas.

Adult↗
PubMed1975

Antimitotic activity of the potent tumor inhibitor maytansine.

Maytansine, at 6x10(-8)M, irreversibly inhibits cell division in eggs of sea urchins and clams. It causes the disappearance of a mitotic apparatus or prevents one from forming if added at early stages. Maytansine does not affect formation of the mitotic organizing center but does inhibit in vitro polymerization of tubulin. Maytansine and vincristine inhibit in vitro polymerization of tubulin at about the same concentrations, but vincristine is about 100 times less effective as an inhibitor of cleavage in marine eggs.

Animals↗
PubMed1984

Effects of vincristine, maytansine, and cis-platinum on behavioral and electrophysiological indices of neurotoxicity in the rat.

The effects of the antineoplastic drugs vincristine, maytansine and cis-platinum were studied to determine the appropriateness of a behavioral and electrophysiological test battery for characterizing the neurotoxicity of such therapeutic compounds. Single- and repeated-dose studies in rats were performed initially, to establish doses for the subchronic neurobehavioral study. Measurements obtained in the subchronic study included body weight, rectal temperature, forelimb and hindlimb grip strengths; performance of a multisensory conditional avoidance response task and other behavioral tests; and a series of evoked responses (ventral caudal nerve action potential, brainstem auditory response and responses from other modalities). The drugs were injected intraperitoneally 5 days per week for 7 weeks. The rats were tested weekly during baseline, treatment and recovery phases. Each drug caused a different pattern of effects, but they all altered body weight, rectal temperature, peripheral nerve conduction velocity, the somatosensory evoked potential and undifferentiated motor activity. cis-Platinum was the most toxic, and maytansine was the least toxic. The results indicated that some elements of the test battery were useful for evaluating the neurotoxicity of anticancer drugs. However, other tests - notably, a test of negative geotaxis and the cortical auditory evoked response - were unreliable.

Action Potentials↗
PubMed1987

Characterization of decomposition products of maytansine.

Analysis of outdated clinical samples of maytansine formulated in mannitol indicated that approximately 40% of the original maytansine content had decomposed. Chromatographic examination of these samples showed the presence of one major and multiple minor decomposition products. The major decomposition product was found to be maysine, a naturally occurring maytansinoid resulting from hydrolytic elimination of the C-3 ester side chain. Four minor decomposition products were isolated with the use of HPLC. All of these decomposition products were found to possess the C-3 ester side chain. However, other structural modifications were noted, especially in the region of the C-9 carbinolamide. Two of the minor decomposition products were tentatively identified as 10-epimaytansine and 9-epimaytansine. One minor decomposition product was found to contain a hydroxyl group at the benzylic C-15 position.

Antineoplastic Agents, Phytogenic↗