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At least 19 recordsLinked to original sources

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↗

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↗

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↗

PubMed1979

Induction of neurofibrillary degeneration following treatment with maytansine in vivo.

The effects of maytansine (MYT), a naturally occurring ansa macrolide and potent antimitotic drug that binds to tubulin, were studied by light and electron microscopy in the central nervous system of rabbits. Respectively, 17 and 5 animals were sacrified at various time intervals following a single intrathecal or intraocular injection of the agent. The rabbits responded to the intrathecal injection with progressively severe weakness. By 19 h following injection the neurons of the cervical spinal cord, medulla and pons showed, by light microscopy, a marked clumping of the Nissl substance, while on the third day and later the nerve cell perikarya and dendrites displayed severe neurofibrillary changes. By electron microscopy several cytological alterations were observed as early as 19 h; among them were the clumping of the rough endoplasmic reticulum, the reduction in number of microtubules, and the presence of a fine, floccular and amorphous material. The perikaryonal and dendritic neurofibrillary changes appeared as tangles and/or bundles of10 nm neurofilaments. In the intraocularly injected rabbits the earliest changes observed in retinal ganglion cells were the severe reduction in microtubule number and the presence of an amorphous material. The neurofibrillary changes seen at later times were comparable with those observed in the cervical cord and brain stem. Although the molecular events occurring between the formation of the intracytoplasmic MYT-tubulin complexes and the accumulation of filaments are not known, the present results indicate that the proliferation of neurofilaments is chronologically preceded by the reduction in number of the microtubules and by the appearance of an amorphous floccular material in the cytoplasm. It is emphasized that despite differences in binding characteristics and physico-chemical properties, maytansine, colchicine and the Vinca alkaloids have, as a common denominator, the property of interfering with the process of utilization of tubulin and in that way they seem to differ from other chemical agents known to induce neurofibrillary degeneration.

Animals↗

PubMed1978

A therapeutic trial of maytansine.

A phase II clinical trial of maytansine, a stathmokinetic ansa macrolide, was undertaken in 70 patients. The maximally tolerated dose was 2.0 mg/m2 repeated at 21-day intervals. Gastrointestinal and central neurologic toxicity were dose limiting. No myelosuppression was noted. Two patients demonstrated transient responses. Therapeutic results from four other clinical trials were reviewed. Although additional clinical trials may be warranted in patients with bladder and small cell carcinoma, at the dose schedule reported, maytansine does not appear to possess a broad spectrum of antitumor activity. Additional clinical trials should be limited.

Adolescent↗

PubMed1978

Early clinical study of an intermittent schedule for maytansine (NSC-153858): brief communication.

Maytansine, an ansa macrolide, was evaluated in an early clinical trial in 40 adult patients with various solid tumors. Severe nausea and vomiting, sometimes associated with watery diarrhea and abdominal cramps, and liver function abnormalities, mainly elevation of serum glutamic--oxaloacetic transaminase levels, together constituted what we considered dose-limiting toxicity. Mild hematologic toxicity (mainly thrombocytopenia), neurotoxicity, and possibly cardiac toxicity were also noted. No antitumor effect was seen. An iv dose of 0.750 mg/m2 on days 1, 3, and 5 (total dose, 2.25 mg/m2) repeated every 4 weeks is recommended for Phase II trials.

Adult↗

PubMed1978

Phase I study of maytansine using a 3-day schedule.

Maytansine, a new ansa macrolide antitumor antibiotic, was administered to 60 patients as part of a phase I study. The doses given ranged from 0.01 (starting level) to 0.9 mg/m2 for 3 days. The toxic effects encountered consisted principally of nausea, vomiting, diarrhea, and occasionally, stomatitis and alopecia. Superficial phlebitis was also encountered and occurred when the drug was diluted in a volume of less than 250 ml. Myelosuppression occurred infrequently; it was almost regularly associated with abnormal liver function tests. Antitumor activity was detected in one patient each with melanoma, breast carcinoma; and head and neck clear cell carcinoma. Further studies are indicated with this compound since it has shown evidence of activity with little or no myelosuppression.

Blood Cell Count↗

PubMed1978

Initial clinical trials of maytansine, an antitumor plant alkaloid.

We have conducted a phase I clinical trial of maytansine, a plant alkaloid with potent tubulin-binding activity. For evaluation of toxicity, the schedule of drug administration consisted of a single iv infusion given every 3 weeks. Dose-limiting toxicity was observed at 2 mg/m2, and was manifested as profound weakness, diarrhea, nausea, and vomiting. Symptoms persisted for 3--14 days after drug administration. No consistent myelosuppression occurred at any dose level. Responses were observed in two patients (one each with non-Hodgkin's lymphoma and ovarian cancer) who were treated on the every-3-week schedule, as well as in two patients with acute lymphocytic leukemia treated with single weekly doses. Three of the four responding patients had received extensive prior treatment with vincristine, and two were clearly resistant to vincristine.

Adolescent↗

PubMed1979

Results of a phase II study of maytansine in patients with breast carcinoma and melanoma.

During the phase I study of maytansine at our institution, some activity was observed against breast carcinoma and melanoma. A phase II study was thus initiated to more thoroughly investigate the activity of this drug against these two tumors. In 33 evaluable patients with melanoma, no complete or partial responses were observed. Twenty-one evaluable patients with breast cancer were entered and only one response (partial) was seen. The toxicity was similar to that observed in the phase I study and consisted mainly of diarrhea, paresthesias, phlebitis, and flu-like symptoms. Myelosuppression was infrequent and was short-lived when it occurred.

Breast Neoplasms↗

PubMed1976