Vindesine Research Articles

Vinca Alkaloid Skin Toxicity: Antidote and Drug Disposition Studies in the Mouse<xref ref-type="fn" rid="FN2">2</xref><xref ref-type="fn" rid="FN3">3</xref>

A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) and vindesine (VDS). With vincristine (VCR) only about 70% of mice developed dose-dependent ulceration. On an equal weight basis, VCR proved to be significantly more toxic than either VBL or VDS (P less than .05 by Student's t-test). Effective local intradermal antidotes to VBL, VDS, and VCR included hyaluronidase, normal saline, and calcium leucovorin (P less than .05 by the Student's Newman-Keuls multiple range test). Mild, topical skin heating significantly reduced VCR ulceration. In contrast, diphenhydramine and sodium bicarbonate were ineffective as local antidotes. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR (P less than .05). Hydrocortisone, vitamin A topical cream, and isoproterenol increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharmacokinetic disposition from the skin and adherent panniculus carnosus muscle. [3H]VBL exhibited two phases of elimination: a rapid early phase [half-life (t 1/2) of approximately equal to 30 min] and a prolonged terminal phase (t 1/2 of approximately equal to 17 hr). The application of heat increased the distributive, early phase by 0.5-2.5 hours and did not enhance the terminal elimination of the drug from skin. Intradermal hyaluronidase significantly reduced the area under the ulceration multiplied by the time curve to one-seventh the control value, the peak [3H]VBL skin concentration to one-half the control value and the terminal [3H]VBL t 1/2 in skin to one-third the control level (P less than .05 by Student's t-test). These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasations.

ENHANCEMENT OF THE ANTITUMOR EFFECTS OF ANTICANCANCER DRUGS BY VERAPAMIL IN HUMAN TUMOR XENOGRAFTS SERIALLY TRANSPLANTED INTO NUDE MICE

Enhancement of the antitumor effects of vincristine (VCR), vindesine (VDS), mitomycin C (MMC) and adriamycin (ADM) by the calcium antagonist, verapamil was investigated using human xenografts serially transplanted into nude mice.Neuroblastoma, rhabdomyosarcoma, and gastric and colonic carscinomas were subcutaneously transplanted into the backs of BALB/C nude mice. VCR, VDS, MMC and ADM with verapamil were administered to the tumor bearing nude mice. The effects of chemotherapy were evaluated by the growth rate curve of the tumor, doubling time, the ratio of mean weight of the treated tumor to that of the control tumor, histological findings and flow cytometric study.Verapamil remarkably enhanced the antitumor activity of VCR in neuroblastoma, VDS in rhabdomyosarcoma and MMC in gastric cancer. Verapamil slightly enhanced the antitumor effect of ADM in gastric cancer and MMC in colonic cancer. In nude mice, the nontoxic and effective dose of verapamil was from 25 mg/kg to 50 mg/kg. This combined chemotherapy of an anticancer drug and verapamil seemed to be effective for tumors transplanted into nude mice, suggesting its clinical applicability.

Phase II study of vindesine in patients with non-small cell lung cancer.

A phase II study of vindesine (VDS) was carried out in 21 patients with non-small cell lung cancer (NSCLC). There were 13 and 8 patients with and without prior chemotherapy, respectively. VDS was administered at a weekly iv dose of 3 mg/m2. Partial response was observed in two of 15 adenocarcinomas and one of 2 adenosquamous cell carcinomas, and the overall response rate was 14.3% (3/21). Myelosuppression, especially leukopenia, was the most common dose-limiting side effect. Neurotoxicity was also a common side effect but the degree was mild. It was concluded that VDS at a dose of 3 mg/m2 every week seems to be active against NSCLC.

Methotrexate-vindesine association in the treatment of head and neck cancer influence of vindesine on methotrexate's pharmacokinetic behavior.

Determination of methotrexate (MTX) kinetics after an IV bolus (50 mg/m2) allows prediction of the steady-state plasma level of this drug during a constant infusion. This prediction allows high-dose MTX (HD-MTX) therapy without major toxicity. Patients with head and neck carcinoma received HD-MTX and vindesine (VDS) infusions concomitantly. The therapeutic survey of these patients showed that the predicted plasma level of MTX was not achieved in the presence of VDS. Moreover, the computed dose of MTX had to be increased by a larger amount if the MTX plasma clearance after the identification IV push was low (less than 9 l/h). In the presence of VDS, the creatinine clearance is lower than when MTX is infused alone, and MTX renal elimination is identical (MTX or MTX + VDS infusions). Thus it seems that the decrease of the MTX plasma level during MTX-VDS infusion could be due to an increase of cellular incorporation.

Interactions of human leukocyte interferon with vinca alkaloids and other chemotherapeutic agents against human tumors in clonogenic assay.

Purified human leukocyte interferon produced by recombinant techniques (IFN-alpha A) was tested in vitro with chemotherapeutic drugs, vinblastine (VLB), vincristine (VCR), vindesine (VDS), vinzolidine (VZL), cis-platinum (PLAT), doxorubicin (DOXO), etoposide (VP-16), and melphalan (MEL). The activity of these agents alone or in combination was tested against various human tumor cell lines, using a modified soft agar clonogenic assay. Three human tumor cell lines (myeloma, RPMI 8226; breast, MCF-7; and colon, WiDR) showed sensitivity to these agents at clinically achievable drug concentrations. Statistically significant synergistic activity against in vitro colony formation was observed with the combination of VLB and IFN-alpha A. An additive or sub-additive effect was usually observed with the other agents tested. Continuous exposure of the 8226 myeloma cell line to both IFN-alpha A and PLAT showed evidence of a more significant potentiation. It is hypothesized that the synergistic effect observed between VLB and IFN-alpha A is due to some of their common mechanisms of action.

Inhibition of murine CFU-C by vindesine: restoration of colony growth by colony stimulating factor.

Vindesine (VDS) is a new vinca-alkaloid related to vinblastine and vincristine that blocks production of the microtubules in the mitotic phase of the cell cycle. Studies were undertaken to investigate the inhibitory effect of VDS on normal murine bone marrow cell proliferation and the possible interactions between this compound and L-cell derived colony stimulating factor (CSF). One X 10(7) murine bone marrow cells were exposed to various concentrations of VDS, ranging from 0.1 to 1.5 micrograms/ml for 1 h at 37 degrees C. Following this period, the cells were plated in agar in the presence of 100 units of CSF. A dose-dependent inhibition of colony formation was noted with increasing doses of the drugs. To determine whether an increased dose of CSF could overcome the inhibitory effect of VDS, further studies compared colony growth in response to 100 and 200 units of CSF. Virtually no inhibition of colony growth was detected in VDS-treated cells exposed to this higher dose of CSF while a dose-dependent reduction in CFU-C was noted with 100 units of CSF. Preincubation of cells with VDS and CSF prevented the inhibition that occurred with VDS alone. The addition of anti-CSF serum during the preincubation phase abolished the protective effect of CSF. The studies show that short-term exposure of marrow cells to VDS causes a dose-dependent inhibition of in vitro colony formation; this inhibition is prevented by increasing doses of CSF in agar culture or by simultaneous preincubation with CSF. The CSF action appears specific as its protective effect is neutralized by antibody to CSF, suggesting a potential role for CSF in preventing the antimitotic activity of VDS.

Localisation and toxicity study of a vindesine-anti-CEA conjugate in patients with advanced cancer.

Safety of administration of a vindesine (VDS)-anti-CEA conjugate and its ability to localise after radiolabelling were investigated in patients with advanced metastatic carcinoma (4 colorectal and 4 ovarian). For imaging, patients received between 230 and 520 micrograms of 131I labelled antibody. In 5, localisation of conjugate was demonstrated, in another it was equivocal and in 2 patients, undetectable. For assessment of safety each patient also received a single dose of conjugate increasing from 1.2 to 42 mg antibody linked to 24 to 1800 micrograms VDS. The in vitro activity of the anti-CEA antibody and its ability to localise in vivo were preserved after conjugation. There was no obvious toxicity or hypersensitivity attributable to either the radiolocalisation or escalated doses of conjugate in any of the patients. The feasibility of the preparation and administration to patients of a vindesine-antibody conjugate has been demonstrated.

Establishment and properties of vincristine-resistant human myelogenous leukemia K562.

A vincristine (VCR)-resistant subline of human K562 myelogenous leukemia was established in vitro, and several clones with different susceptibilities to VCR were isolated by the limiting dilution technique. The most resistant clone (H-1) had a 17-fold greater resistance to VCR when compared to the parent K562 cells. The clone gradually lost the resistance during prolonged culture in vitro. These clones generally accumulated smaller amounts of VCR in their cells as compared to the parent cells. The size of H-1 clone cells was almost the same as that of the parent cells. The numbers of potential binding sites of VCR in the K562 cells and the resistant H-1 clone were almost the same. Similar results were obtained for P388 and its VCR-resistant subline. The cells derived from the VCR-resistant H-1 clone were highly cross-resistant to vindesine and moderately resistant to vinblastine. Cells derived from clone H-1 exhibited marginal degrees of cross-resistance to adriamycin, maytansine and VP-16-213, whereas VCR-resistant P388 leukemia cells exhibited significant resistance to these agents, especially to maytansine.

Treatment of acute lymphoblastic leukemia in adults with combination chemotherapy incorporating vindesine and prednisolone.

Seven adult patients with acute lymphoblastic leukemia (ALL) were treated with induction regimen incorporating vindesine (VDS) and prednisolone (VDS-P). After achieving complete remission, multidrug regimens for remission consolidation and maintenance were given. All patients achieved complete remission including five cases of continuous complete remission.

Vindesine effect in myeloid leukemia

Vindesine (VDS), a semisynthetic vinca alkaloid derivative, was given weekly at a dose of 3 mg/m2 as single-agent chemotherapy to seven patients with chronic myeloid leukemia (CML), 17 patients with chronic myeloid leukemia in blastic metamorphosis (CML/BM), and 12 patients with acute nonlymphocytic leukemia (ANLL). A substantial and rapid decrease of leukemic cells was obtained in 31 of 36 patients, and this was independent of cell phenotype and morphology. VDS may improve the results of polychemotherapy of ANLL, and is useful for palliative treatment of CML/BM.

Establishment of Vincristine-resistant and vindesine-resistant lines of murine lymphoblasts in vitro and characterisation of their patterns of cross-resistance and drug sensitivities.

Clinical evidence suggests some lack of cross resistance between vincristine (VCR) and vindesine (VDS). To investigate this phenomenon experimentally, drug-resistant L5178Y lymphoblast cell lines have been derived in vitro. These lines, under conditions of continuous drug exposure, exhibit a 50-fold order of resistance. Resistance appears due, at least in part, to impaired cellular drug accumulation and retention. Exposure of these resistant cells to VCR or VDS for 24 h showed that the presence or absence of cross resistance was dose-dependent, being most noticeable at low concentrations (less than 0.5 ng/ml) and absent at higher drug levels. Cross resistance also showed some dose-dependency for vinblastine and formyl-leurosine, but this was not seen with other drugs. Marked and complete cross resistance at all concentrations tested was noted with adriamycin and 4'-epiadriamycin in both resistant lines, which, however, retained the same sensitivities as the parent line to VM26, VP-16-213, 5-fluorouracil, and methotrexate. Responses to actinomycin D and mAMSA differed in these two resistant lines. VDS-resistant cells exhibited cross resistance to both drugs, whilst VCR-resistant cells showed only slight resistance to actinomycin D whilst retaining full sensitivity mAMSA. This observation that cross resistance between VCR and VDS is not invariable in vitro appears to reflect clinical experience.

Cross-Resistance of Cultured Murine Leukemia Vincristine-Resistant P388 Cells to Vinblastine, Vindesine, and Bis(N-ethylidene vindesine) Disulfide, Disulfate23

Cultured P388 leukemia cells derived from vincristine (VCR)-resistant cell populations developed in vivo in (C57BL X DBA/2)F1 mice (P388/VCR) were cross-resistant to vinblastine (VLB), vindesine (VDS), and bis(N-ethylidene vindesine)disulfide, disulfate (bis-VDS). Cross-resistance was a function of concentration and time of exposure. Cultured P388/VCR cells were more sensitive to 6.1x10-5Mbis- VDS than to 6.1x10-5MVDS or to 6.1x10-5MVLB. Cultured P388 cells derived from VCR-sensitive P388 leukemia passaged in vivo (P388/0)were significantly more sensitive to VDS and bis-VDS than to VLB. This degree of difference in sensitivity was also a function of concentration and time of exposure.

Vinblastine, vincristine and vindesine: Anti-invasive effect on MO 4 mouse fibrosarcoma cells in vitro

Inhibition of the invasiveness of MO 4 mouse fibrosarcoma cells by the vinca alkaloids, vinblastine (VLB), vincristine (VCR) and vindesine (VDS), has been examined in vitro. At doses between 0.006 μ g/ml (minimal effect) and 0.1 μg/ml (complete inhibition) these drugs interfered with the invasion of MO 4 cells from an aggregate confronting a fragment of embryonic chick heart in three-dimensional culture. We have also examined the effect of these drugs on the following activities of MO 4 cells: growth, directional migration and assembly of the cytoplasmic microtubule complex. Growth and directional migration were affected by the same doses of vinca alkaloids as invasion. In contrast with the vinca alkaloids, 5-fluorouracil at 1 μ g/ml inhibited growth but allowed directional migration and invasion. At a dose of 0.3 μ g/ml VLB, VCR and VDS interfered with the assembly of cytoplasmic microtubules, as visible after immunocytochemical staining with tubulin antiserum. Ultrastructural analysis demonstrated that inhibition of invasion in three-dimensional culture corresponds with abolishment of the cytoplasmic microtubule complex. Anti-invasive concentrations of VLB, VCR and VDS represent clinically achievable plasma concentrations. We concluded that the anti-invasive effect of the vinca alkaloids may contribute to their antitumor activity.

Influence of vindesine on the lytic phase of mouse natural cytotoxicity against human leukemic cells.

Vindesine (VDS), a structural analogue of Vinca Alkaloids, was found to increase the NK-mediated cytolytic effects of mouse lymphocytes against human K562 target cells in a 18-hr assay. Pretreatment of effector or target cells with the drug did not affect substantially the NK reaction. The phenomenon has been detected using splenocytes of either congenitally athymic or conventional euthymic mice of different strains. Effector lymphocytes deprived of cells adherent to plastic surface or to nylon-wool column were still competent for drug-mediated increase of NK function. It is suggested that modification of the membrane make-up of effector or target cells reversibly induced by VDS, would promote higher NK-mediated cytolytic effects.

Vindesine in the treatment of refractory hematologic malignancies: A phase II study

A phase II evaluation of vindesine (VDS) was carried out in 46 patients with hematologic malignancies refractory to conventional chemotherapy. Two VDS schedules were employed (at random): (A) a weekly bolus (5 mg/m 2 i.v. × 4); (B) fractionated daily injections (0.5 mg/m 2 i.v. q. 12 h × 10, course to be repeated after 10–15 days). Complete and partial remissions were observed in acute lymphocytic leukemia ( 3 14 patients), acute non-lymphocytic leukemia ( 2 12 patients), chronic myelocytic leukemia in blastic crisis ( 4 12 patients) and non-Hodgkin's lymphoma ( 4 8 patients). Responses were seen with higher frequency in patients treated with the weekly bolus (42.8 vs 16%). Myelosuppression was the most relevant side effect in both schedules. Neurotoxicity occurred infrequently and was generally mild in degree. Further trials with VDS in combination with other drugs are recommended in hematologic malignancies.

Comparative Cell Killing and Kinetic Effects of Vincristine or Vindesine in Mammalian Cell Lines

Survival curves for several monolayer and suspension cultures following 24-hour exposures to various vincristine (VCR) or vindesine (VDS) concentration were all of the exponential-plateau type. Cytotoxicity increased with duration of exposure in hamster NIL8 cells and was comparable for both drugs. Murine L5178Y cells, although 200 times more sensitive than NIL8 cells, also showed similar sensitivities to VCR and VDS. Murine neuroblastoma cells proved approximately fivefold less sensitive to VDS than VCR, whereas qualitative and quantitative differences in the activity of these two drugs were noted in human neuroblastoma cells. The lethal effects of VCR and VDS were exerted solely on logarithmically growing NIL8 cells in the S-phase. Plateau-phase human neuroblastoma cells were also significantly less sensitive to both drugs than were logarithmically growing populations, were cell kill occurred during the S-phase. Complete mitotic arrest, induced by a 24-hour exposure to VCR or VDS, was only partially reversible, whereas rapid and complete reversibility occurred after only 5 hours of drug exposure.

A comparison of combination chemotherapy using vindesine or vincristine with adriamycin in the treatment of advanced breast carcinoma

Vindesine (VDS) as a single agent achieved 2 complete remissions and 4 partial responses in 21 patients with advanced breast carcinoma (overall response rate: 29%) (2). Neurotoxicity occurred in 40% of the patients but was usually mild and non-progressive. As a result of this study, a controlled randomized combination chemotherapy trial was started in patients with advanced breast cancer, comparing vindesine (3 mg/m2, Days 1 and 8), with vincristine (VCR) (1.4 mg/m2 I.V., Days 1 and 8), each in combination with adriamycin (40 mg/m2, Days 1 and 8), repeating each regimen at monthly intervals. So far 9 out of 15 patients treated with the VCR combination have achieved a response (60%), compared with 11 out of 16 patients on the VDS regimen (69%). Five patients have developed neurotoxicity severe enough to reduce or stop treatment with VCR, compared with 2 patients treated with VDS. Seven patients have developed leucopenia (WBC less than 2500) on the VCR combination and 8 on the VDS combination. The trial is continuing. Vindesine (VDS) as a single agent achieved 2 complete remissions and 4 partial responses in 21 patients with advanced breast carcinoma (overall response rate: 29%) (2). Neurotoxicity occurred in 40% of the patients but was usually mild and non-progressive. As a result of this study, a controlled randomized combination chemotherapy trial was started in patients with advanced breast cancer, comparing vindesine (3 mg/m2, Days 1 and 8), with vincristine (VCR) (1.4 mg/m2 I.V., Days 1 and 8), each in combination with adriamycin (40 mg/m2, Days 1 and 8), repeating each regimen at monthly intervals. So far 9 out of 15 patients treated with the VCR combination have achieved a response (60%), compared with 11 out of 16 patients on the VDS regimen (69%). Five patients have developed neurotoxicity severe enough to reduce or stop treatment with VCR, compared with 2 patients treated with VDS. Seven patients have developed leucopenia (WBC less than 2500) on the VCR combination and 8 on the VDS combination. The trial is continuing.

Phase I and II studies of vindesine

Phase I and II studies of vindesine

Toxicity and pharmacology of bolus vindesine injection and prolonged vindesine infusion

Vindes ine is a chemica l ly der ived, s t ruc tura l ana log of vinblas t ine sulfate. I t has been shown to be active against a w ide range of exper imenta l an ima l tumors (3). Phase I trials of vindesine in m a n have ind ica ted that a weekly dose of 2 -4 m g / m 2 given by in t ravenous bolus is well to lera ted (1, 2). A l though weekly in t ravenous bolus vindesine infusion has been the most f requen t ly used schedule of d r u g admin i s t ra t ion , p re l imina ry s t u d i e s b y Mathd et al. (4) have suggested tha t a 48-h infusion o fv indes ine m a y be more effective than a weekly bolus inject ion schedule in cer ta in clinical situations. We have adrnmlstered~ v~r!desme to 26 pat ients wl th various m a h g n a n c l e s using e i ther the weekly bolus injection schedule or a 48-h infusion schedule . This pape r presents the p re l imina ry results of our clinical studies using these t~4o d r u g admin i s t r a t ion schedules. T h e results o f pha rmaco log ic studies c o m p a r i n g seriam vindesine levels ach ieved wi th a 48-h d r u g infusion a re c o m p a r e d with those of bolus d rug admin is t ra t ion . M e a s u r e m e n t s o f rena l and bi l iary excre t ion of vindesine are also presented.

Uptake of Vinca alkaloids into mammalian nerve and its subcellular components.

Three Vinca alkaloids, vinblastine (VLB), vincristine (VCR), and vindesine (VDS), were recently found to affect axoplasmic transport to different degrees, with VCR the most potent. The uptake of these three species by desheathed cat sciatic nerves in vitro was determined by using tritium-labeled derivatives. In a sucrose medium, the uptake of VCR was found to be three to four times greater than that of VLB and VDS, which is in accord with the neurotoxicity of VCR. Uptake of VCR was dependent on Ca2+ concentration in the medium. Removal of Ca2+ from the incubation medium reduced the uptake of VCR, without having much effect on VLB or VDS uptake. The uptake of all three Vinca agents into nerve in a saline medium was about 50% of that in a sucrose medium, and elimination of Ca2+ from the saline incubation medium did not result in any significant change in uptake. High Ca2+ concentrations (100 mM) in the incubation medium, which cause a block of axoplasmic transport, did not change the total uptake of the Vinca alkaloids to any significant degree. The amount of labeled alkaloid found in the soluble fraction was, however, decreased by 50%. There was an increase in the amount present in the particulate fraction, caused, most likely, by an aggregation of vinca-binding components. The amount of VCR associated with tubulin-containing components isolated by gel filtration of the soluble fraction increased twofold when the nerves were exposed to a high-Ca2+ medium, as might be expected of a microtubule disassembly. Exposure of the nerve to low temperatures (0 degrees-4 degrees C) for 90 min did not show any effect on the total uptake of Vinca alkaloids.