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PubMed1979

Adriamycin, bleomycin, vinblastine and imidazole carboxamide (ABVD) therapy for advanced Hodgkin's disease resistant to mustine, vinblastine, procarbazine and prednisolone (MVPP).

Forty-one previously treated patients with advanced Hodgkin's disease were treated with a combination chemotherapy regimen -- ABVD (adriamycin, bleomycin, velbe/vincristine, imidazole carboxamide). Complete remission was achieved in three patients (7%), partial remission in 23 (56%), and no response in 15 patients (37%). The median survival of the group was 12 months from the start of therapy. Survival correlated with response to treatment. No apparent benefit resulted from giving more than six courses of therapy (3 months' treatment time). There was no serious haematological toxicity in patients without bone marrow disease, and bleomycin and adriamycin toxicity was not apparent clinically or at autopsy in the dosages employed in the regime. Alopoecia was very frequent. The role for ABVD, other than as a primary induction regimen, appears to be in conjunction with other regimens in the induction of patients with adverse features at presentation or during induction; or in the salvage and palliation of patients who demonstrate a response but fail to achieve remission, either initially or at relapse, with MOPP (mustine, vincristine rpocarbazine, and prednisolone) or MVPP (mustine, vinblastine, procarbazine and prednisolone.

Adolescent↗
PubMed1998

Effect of vinblastine on cell membrane fluidity in vinblastine-sensitive and -resistant HeLa cells.

The electron paramagnetic resonance method (EPR) was used to study the effects of vinblastine (VLB) on cell membrane fluidity in wild-type HeLa cells (HeLa K) and its subclone, which is resistant to several drugs (HeLa CA). HeLa CA cells, obtained by treatment of HeLa K with CDDP, were found to be more resistant to VLB than to CDDP. The experimentally observed EPR spectra were correlated with the calculated spectra obtained by computer simulation. The results indicate that the cell membrane of HeLa K and HeLa CA cells is heterogeneous and can be described with at least three types of coexisting domains with different fluidity characteristics. The two more fluid domains of HeLa CA cells were found to be more fluid than in HeLa K cells. The fluidity of the less fluid domain remained unchanged but its portion in the membrane was increased. VLB treatment did not affect the membrane fluidity of HeLa CA cells significantly. On the other hand, 1 h of treatment of HeLa K cells with 1 ng/ml VLB did not change the fluidity characteristics of membrane domains but decreased the portion of the less fluid domains. This was also reflected in an average increase of the entire membrane fluidity. The observed changes were detected at VLB concentrations which were far below the cytotoxic level.

Antineoplastic Agents, Phytogenic↗
PubMed1992

A randomized prospective study of cisplatin and vinblastine versus cisplatin, vinblastine and mitomycin in advanced non-small cell lung cancer.

From June 1986 to February 1989, 103 patients with advanced non-small cell lung cancer, with no previous chemotherapy, were randomized to receive either a combination of cisplatin and vinblastine (group A) or the same combination with the addition of mitomycin (group B). In group A, 15/48 evaluable patients had objective responses, as did 8/45 in group B. The median survivals were 35 and 32 weeks, respectively. The median survival of patients with response or stable disease was 43 weeks. Response and survival did not differ significantly between treatment groups. The addition of mitomycin to the two-drug combination showed no major therapeutic benefit, while bone marrow toxicity was increased. Three patients in group B died of sepsis. Among the different patient characteristics, disease stage, performance status and response had influence on survival.

Adult↗
PubMed1999

Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer.

PURPOSE: The combination of interferon alfa-2a (IFNalpha2a) plus vinblastine (VLB) induces objective tumor responses in patients with advanced renal cell cancer. However, no prospective randomized trial has shown that this treatment prolongs overall survival. We compared overall survival after treatment with IFNalpha2a plus VLB versus VLB alone in patients with advanced renal cell cancer. PATIENTS AND METHODS: We prospectively randomized 160 patients with locally advanced or metastatic renal cell cancer to receive either VLB alone or IFNalpha2a plus VLB for 12 months or until progression of disease. In both groups, VLB was administered intravenously at 0.1 mg/kg every 3 weeks, and in the combination group IFNalpha2a was administered subcutaneously at 3 million units three times a week for 1 week, and 18 million units three times a week thereafter for the second and subsequent weeks. For patients unable totolerate IFNalpha2a at 18 million units per injection, the dose was reduced to 9 million units. RESULTS: Median survival was 67.6 weeks for the 79 patients receiving IFNalpha2a plus VLB and 37.8 weeks for the 81 patients treated with VLB (P =.0049). Overall response rates were 16. 5% for patients treated with IFNalpha2a plus VLB and 2.5% for patients treated with VLB alone (P =.0025). Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters, but no toxic deaths were reported. CONCLUSION: The combination of IFNalpha2a plus VLB is superior to VLB alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. This is the first study to demonstrate that survival can be prolonged by using IFNalpha2a for these patients.

Adult↗
PubMed1994

[Treatment outcome of advanced Hodgkin's disease based on using an alternating program ChLVPP (chlorambucil, vinblastine, procarbazine, prednisone) and ABV (doxorubicin, bleomycin, vinblastine)].

Twenty nine patients (7 women, 22 men) with III and IV stage of Hodgkin's disease were treated according to alternating programme ChLVPP/ABV. The results were evaluated in 27 patients. Complete remission was obtained in 41% (11 patients), partial remission in 22% (6 patients). Applied treatment revealed a relatively small toxicity.

Adult↗
PubMedDate not supplied

Treatment of Hodgkin's disease in children with VAMP (vinblastine, adriamycin, methotrexate, prednisone) and VEPA (vinblastine, etoposide, prednisone, adriamycin).

Treatment of Hodgkin's disease in children should be directed at maximizing cures and minimizing the long-term effects of alkylating agents, anthracyclines, and bleomycin. In this study methotrexate and etoposide were used in the VAMP/VEPA regimens to treat 60 clinically staged pediatric patients with Hodgkin's disease. Twenty-nine patients with stages I-IIA received four courses of VAMP plus low-dose radiotherapy. Thirty-one IIA bulky disease and IIB-IVB patients received four or six courses of VEPA plus low-dose radiotherapy. There were 6 partial remissions after the completion of chemotherapy and all of these patients relapsed, but 4 were successfully salvaged with ABMT. Two patients have died. The 3.1-year overall survival rate is 97% (100% VAMP, 94% VEPA) and the event-free survival rate is 88% (97% VAMP, 77% VEPA). These results suggest that VAMP is a reasonable treatment for low stages of Hodgkin's disease, but more advanced disease is not adequately treated by VEPA and low-dose radiotherapy.

Adolescent↗
PubMed1998

Reversal of vinblastine transport by chlorpromazine in membrane vesicles from multidrug-resistant human CCRF-CEM leukaemia cells.

The mechanism of action of 2-chlorpromazine (2-chloro-10-(3-dimethylaminopropyl)-phenothiazine) as a reversal agent for P-glycoprotein-mediated multidrug resistance was investigated using inside out-orientated membrane vesicles prepared from vinblastine-resistant human CCRF-CEM leukaemia cells (VBL1000). 2-Chlorpromazine (10 microM) completely inhibited ATP-dependent P-glycoprotein-mediated vinblastine accumulation in the vesicles. Whereas in the absence of added ligands VBL transport was described by a hyperbolic function of vinblastine concentration, in the presence of 2-chlorpromazine vinblastine transport was a sigmoidal function. 2-Chlorpromazine was shown previously [Syed SK, Christopherson RI and Roufogalis BD (1996) Biochem Mol Biol Int 39: 687-696] to be actively transported into vesicles from multidrug-resistant cells. Colchicine (10 microM) and phenoxybenzamine (10 microM) blocked vinblastine transport but had no effect on 2-chlorpromazine transport into vesicles. The results were consistent with a two-state concerted model in which P-glycoprotein exists in two conformational states, P(A) and P(B), where 2-chlorpromazine is transported by the conformer, P(A), and vinblastine by the conformer, P(B). In the presence of 2-chlorpromazine, the conformer P(A) predominates and vinblastine transport is inhibited. Addition of 2-chlorpromazine during the steady state of vinblastine accumulation blocked uptake and resulted in enhanced vinblastine efflux from the vesicles. The findings were similar when vinblastine was added at the steady state of 2-chlorpromazine transport. We propose a minimal kinetic model whereby in these preloaded vesicles the complex VV.P(A).CC is formed, where two internal binding sites of P-glycoprotein (P(A)) are occupied by vinblastine (V) and the two external sites are occupied by 2-chlorpromazine (C). When the two binding sites on both the inside and outside of P-glycoprotein are saturated with ligands vinblastine is effluxed at a very rapid rate, and vice versa when vesicles are preloaded with 2-chlorpromazine and vinblastine is added outside. These unexpected observations and the concerted model developed provide an alternative mechanism of action for reversal agents that sensitize multidrug-resistant cancer cells to anti-cancer drugs.

Biological Transport↗
PubMed2002

A prostate-specific antigen (PSA)-activated vinblastine prodrug selectively kills PSA-secreting cells in vivo.

Currently, there is no therapy for men with androgen-refractory prostate cancer that substantially extends survival. This report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains a peptide bond that can be hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as vinblastine-conjugate) is minimally toxic to cells in culture which do not express PSA. In the presence of PSA, the peptide moiety is hydrolyzed, generating several highly toxic metabolites that contain vinblastine. Animals bearing PSA-positive human prostate tumors that were treated with the vinblastine-conjugate experienced a >99% reduction in PSA serum level. In contrast, animals bearing PSA-positive human prostate tumors treated with the cytotoxic metabolites derived from the PSA hydrolysis of the vinblastine-conjugate showed a nonsignificant change in both PSA and tumor weight values. The cell killing activity of the vinblastine-conjugate is PSA dependent because animals bearing non-PSA-producing human tumor xenografts had a nonsignificant increase in tumor weight after vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP tumor-bearing nude mice were conducted with animals treated for 5 consecutive days with various doses of either the vinblastine-conjugate or a PSA-generated toxic metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment resulted in 10-70% mortality with a very slight effect on tumor growth. In contrast, vinblastine-conjugate treatments resulted in no mortality, good to excellent antitumor efficacy, very slight to slight peripheral neuropathy and myelopathy, and slight to severe testicular degeneration. Similar treatment of beagle dogs with the vinblastine-conjugate showed even less toxicity. These data support the use of the PSA-hydrolyzable vinblastine-conjugate as an experimental therapy for prostate cancer in man.

Animals↗
PubMed1985

Differential cellular retention of vincristine and vinblastine by cultured human promyelocytic leukemia HL-60/Cl cells: the basis of differential toxicity.

Differential toxicity of vincristine and vinblastine against cells of a cloned subline of human promyelocytic leukemia (HL-60/Cl) was dependent on exposure conditions. During continuous exposures of 48 h, vincristine and vinblastine were equitoxic with drug concentrations that inhibited proliferation rates by 50% of 7.6 and 8.1 nM, respectively. When cells were subjected to 4-h exposures and transferred to drug-free medium, the drug concentration of vinblastine that inhibited proliferation rates by 50% (1.1 microM) was significantly greater than that of vincristine (41 nM). Analysis by flow cytometry of the effects of equitoxic drug exposures on cell-cycle progression suggested that vincristine and vinblastine acted by the same mechanism (G2-M phase inhibition). [3H]Vincristine and [3H]vinblastine were bound to serum proteins in growth medium to the same extent (25%) over a wide range of concentrations, and the amounts of "free" extracellular drug did not decrease during prolonged exposures. Analysis by high-performance liquid chromatography of extracts of cultures incubated with growth-inhibitory concentrations of [3H]vincristine or [3H]vinblastine indicated little, if any, metabolism of either drug by cells or culture fluids; after 24 h, 85-95% of radioactivity was recovered from cells or growth medium as unchanged vincristine or vinblastine. At concentrations from 6 nM to 6 microM, vinblastine entered cells rapidly, reaching maximum levels within 0.5-2 h, and the relationship between maximal cell-associated drug and extracellular free vinblastine was linear. Although uptake of vincristine was slower than that of vinblastine, the cellular content of vincristine reached that of vinblastine during prolonged (12-24 h) exposures, and the amounts of cell-associated drug, relative to extracellular drug concentrations, indicated considerable "concentrative" accumulation (intra: extracellular ratios, greater than 100). When drug exposures were ended by transfer of cells to drug-free medium, vinblastine was released from cells more rapidly and to a greater extent than vincristine, independent of whether exposures were 4 or 24 h. Rates of uptake and release of vinblastine (50 nM) were unaffected by depletion of cellular adenosine triphosphate, suggesting that rapid release was not mediated by an energy-dependent efflux system.

Adenosine Triphosphate↗
PubMed1981

The reversible binding of vinblastine to platelets: implications for therapy.

The ability of platelets to adsorb vinblastine has been used to treat patients with immune thrombocytopenia. It is hypothesized that the drug-platelet complex is coated with antibody, taken up by macrophages which are then destroyed by the drug. We gave 16 courses of vinblastine-platelets to six patients with immune thrombocytopenia. Only one patient responded, and therefore we examined possible reasons for the lack of benefit. Using 3H-vinblastine, the kinetics of vinblastine binding to platelets was studied in vitro. The binding of vinblastine to both human and rabbit platelets was identical with maximal binding occurring within 10 min at 600 microgram/ml vinblastine. Similarly, the plasma half-life of vinblastine in rabbits was close to that reported for man, and therefore, in vivo binding of vinblastine to platelets in rabbits was considered a suitable model for man. Homologous donor rabbit platelets were labeled with 51Cr alone, 51Cr plus vinblastine, or 3H-vinblastine and infused into recipient rabbits. Vinblastine had no effect on 51Cr survival, but all measureable vinblastine had left the platelets within 2 hr of the infusion. These observations suggest that delivery of the vinblastine to the macrophages depends on the platelets being phagtocytized before the drug leaves the platelets. This would be likely to occur only in those patients with severe immune thrombocytopenia. Further investigations into this treatment should be directed at methods to maintain the drug within the platelet.

Adsorption↗
PubMed1990

Kinetic analysis of tubulin exchange at microtubule ends at low vinblastine concentrations.

We have investigated the effects of vinblastine at micromolar concentrations and below on the dynamics of tubulin exchange at the ends of microtubule-associated-protein-rich bovine brain microtubules. The predominant behavior of these microtubules at polymer-mass steady state under the conditions examined was tubulin flux, i.e., net addition of tubulin at one end of each microtubule, operationally defined as the assembly or A end, and balanced net loss at the opposite (disassembly or D) end. No dynamic instability behavior could be detected by video-enhanced dark-field microscopy. Addition of vinblastine to the microtubules at polymer-mass steady state resulted in an initial concentration-dependent depolymerization predominantly at the A ends, until a new steady-state plateau at an elevated critical concentration was established. Microtubules ultimately attained the same stable polymer-mass plateau when vinblastine was added prior to initiation of polymerization as when the drug was added to already polymerized microtubules. Vinblastine inhibited tubulin exchange at the ends of the microtubules at polymer-mass steady state, as determined by using microtubules differentially radiolabeled at their opposite ends. Inhibition of tubulin exchange occurred at concentrations of vinblastine that had very little effect on polymer mass. Both the initial burst of incorporation that occurs in control microtubule suspensions following a pulse of labeled GTP and the relatively slower linear incorporation of label that follows the initial burst were inhibited in a concentration-dependent manner by vinblastine. Both processes were inhibited to the same extent at all vinblastine concentrations examined. If the initial burst of label incorporation represents a low degree of dynamic instability (very short excursions of growth and shortening of the microtubules at one or both ends), then vinblastine inhibits both dynamic instability and flux to similar extents. The ability of vinblastine to inhibit tubulin exchange at microtubule ends in the micromolar concentration range appeared to be mediated by the reversible binding of vinblastine to tubulin binding sites exposed at the polymer ends. Determination by dilution analysis of the effects of vinblastine on the apparent dissociation rate constants for tubulin loss at opposite microtubule ends indicated that a principal effect of vinblastine is to decrease the dissociation rate constant at A ends (i.e., it produces a kinetic cap at A ends), whereas it has no effect on the D-end dissociation rate constant.

Animals↗
PubMed1976

In vitro studies on the nature of vinblastine inhibition of thyroid secretion.

The effects of vinblastine on thyroid secretion have been studied in mouse thyroid glands in vitro. Inhibition of the secretory response to TSH was observed within the first 30 min of exposure to vinblastine and was largely complete after 1 h. Inhibition of colloid droplet formation and hormonal radioiodine release was comparable for both TSH and cyclic AMP stimulation. No reversal of inhibition was seen when thyroids exposed to vinblastine were subsequently washed 2 or 4 h in vinblastine free mediu, nor could previous vinblastine inhibition be overcome by high levels of TSH or dibutyryl cyclic AMP. Ultrastructural effects of vinblastine (1 X 10(-5)M) were studied under conditions similar to those used to demonstrate inhibition of secretion. Microtubules present in thyroids incubated in control medium were reduced after 30 min and almost completely abolished after 1 or 2 h exposure to vinblastine. No other reproducible structural changes were seen. A higher concentration of vinblastine (5 X 10(-5)M), however, produced lysosomal clumping and the formation of numerous vinblastine crystalloids. Uptake and washout of [3H]-vinblastine were studied with both phases showing fast and slow components. The initial uptake phase (T1/2 approximately 12 min) correlates well with the disappearance of microtubules and the inhibition of thyroid secretion. A prolonged washout component (T1/2 = 10-18 h) may account for the irreversibility of vinblastine inhibition of in vitro thyroid secretion. It is concluded that inhibition of thyroid secretion produced by vinblastine is consistent with its actions on thyroidal microtubules.

Animals↗