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PubMed1991

Target organ toxicity and leukopenia in Fischer 344 rats given intravenous doses of vinblastine and desacetyl vinblastine.

The toxicity and leukopenia produced by vinblastine or desacetyl vinblastine were established in 1-month studies in rats. Groups of male Fischer 344 rats were given weekly intravenous doses of vinblastine or desacetyl vinblastine at doses of 0.08, 0.16, 0.32, 0.64, or 1.28 mg/kg. The target organ toxicity was similar for both compounds. Decreased cell production in the thymus, testes, and bone marrow was produced in the animals of the two highest dose groups for both compounds with the degree of severity greater in the highest dose group. All high dose rats (1.28 mg/kg) given desacetyl vinblastine and three rats given vinblastine died prior to study termination. Body weight loss was more pronounced in high dose rats given desacetyl vinblastine, but at lower doses there were no significant differences in body weight reduction for rats receiving either compound. Leukopenia occurred at all dose levels of 0.32 mg/kg and higher. During the first 2 weeks of the study, rats given 1.28 mg/kg of desacetyl vinblastine had a greater leukopenic response than rats given 1.28 mg/kg of vinblastine. It is concluded that both compounds produced similar target organ toxicity and leukopenia without deaths at doses of 0.32 and 0.64 mg/kg given once a week for 4 weeks. At the high dose (1.28 mg/kg) desacetyl vinblastine was more toxic than vinblastine resulting in greater mortality and body weight reduction.

Animals↗

PubMed1997

Relation between the turnover number for vinblastine transport and for vinblastine-stimulated ATP hydrolysis by human P-glycoprotein.

Considerable uncertainty surrounds the stoichiometry of coupling of ATP hydrolysis to drug pumping by P-glycoprotein, the multidrug transporter. To estimate relative turnovers for pumping of the drug vinblastine and ATP hydrolysis, we began by measuring the number of P-glycoprotein molecules on the surface of murine NIH3T3 cells expressing the human MDR1 gene. Fluorescence of cells treated with monoclonal antibody UIC2 was determined as a function of (i) amount of antibody at a fixed number of cells and (ii) increasing cell number at constant antibody. The two together gives 1.95 x 10(6) P-glycoprotein molecules/cell. Initial uptake rates of vinblastine +/- verapamil measure the ability of P-glycoprotein to extract vinblastine from the plasma membrane before it enters the cell. As a function of [vinblastine] at 37 degrees C, they give the maximum rate of this component of outward pumping as 2.1 x 10(6) molecules s-1 cell-1 or a turnover number of 1.1 s-1. Initial rates of one-way efflux as a function of [vinblastine] at 25 degrees C +/- glucose give the maximum rate of this component of pumping as 0.59 x 10(6) molecules s-1 cell-1. The ratio of ATPase activity of P-glycoprotein at 37 and 25 degrees C is 4.6. Appropriating this ratio for pumping, maximum one-way efflux at 37 degrees C is 4.6 x 0.59 = 2.7 x 10(6) molecules s-1 cell-1, a turnover number of 1.4 s-1. The vinblastine-stimulated ATPase activity of P-glycoprotein has a turnover number of 3.5 s-1 at 37 degrees C, giving 2.8 molecules of ATP hydrolyzed for every vinblastine molecule transported in a particular direction. These calculations involve several approximations, but turnover numbers for pumping of vinblastine and for vinblastine-stimulated ATP hydrolysis are comparable. Thus, ATP hydrolysis is probably directly linked to drug transport by P-glycoprotein.

3T3 Cells↗

PubMed1986

Transient vinblastine-induced thrombocytopenia during chemotherapy with vinblastine, cis-platinum and bleomycin.

An early, transient drop in peripheral blood platelets to a mean nadir value of 49% (range 31-83%) of the pretreatment value was seen in 31 patients during chemotherapy with cis-platinum, vinblastine and bleomycin (PVB). The mean number of platelets dropped by 22% during the first 24 h after the start of chemotherapy, nadir value was seen after 3 d, with recovery to 107% of pretreatment level on d 14-15. Platelet survival studies during PVB chemotherapy showed shortened platelet survival time and indicated increased destruction of platelets. Identical patterns of early, transient thrombocytopenia were seen in 6 patients treated with vinblastine only. The early fall in circulating platelets did not predict subsequent serious thrombocytopenia. There were no bleeding episodes in the 37 patients studied here, but the early thrombocytopenia seen after vinblastine therapy may possibly be of clinical importance in critically ill patients at risk for bleeding episodes. In rats, an early drop in circulating platelets occurred after a high dose of vinblastine, but not after bleomycin. Addition of bleomycin to vinblastine did not increase the vinblastine-induced thrombocytopenia. It is concluded that the early drop in peripheral blood platelets during chemotherapy with PVB is due to vinblastine.

Animals↗

PubMed1975

The mechanism of action of vinblastine. Binding of [acetyl-3H]vinblastine to embryonic chick brain tubulin and tubulin from sea urchin sperm tail outer doublet microtubules.

Tritium-labeled viblastine, specific activity 107 Ci/mol, was prepared by acetylation of desacetylvinblastine with [3H]acetic anhydride, and has been employed in a study of vinblastine binding to tubulin. There are two high affinity vinblastine-binding sites per mole of embryonic chick brain tubulin (KA = 3-5 X 10(5) l./mol). Binding to these sites was rapid, and relatively independent of temperature between 37 and 0degreeC. Vincristin sulfate and desacetylvinblastine sulfate, two other active vinca alkaloid derivatives, competitively inhibited the binding of vinblastine. The inhibition constant for vincristine was 1.7 X 10(-5) M; and for desacetylvinblastine, 2 X 10(-5) M. The vinblastine binding activity of tubulin decayed upon aging, but this property was not studied in detail. Vinblastine did not depolymerize stable sea urchin sperm tail outer doublet microtubules, nor did it bind to these microtubules. However, tubulin solubilized from the B subfiber of the outer doublet microtubules possessed the two high affinity binding sites (KA = 1-3 X 105 l./mol). These data suggest that vinblastine destroys microtubules in cells primarily by inhibition of microtubule polymerization, and does not directly destroy preformed microtubules.

Animals↗

PubMed1991

Nanoparticles as drug carriers for vinblastine. Acute toxicity of vinblastine in a free form and associated to polybutylcyanoacrylate nanoparticles.

The possibility of reducing toxicity of Vinblastine by fixing it in polybutyl-2-cyanoacrylate nanoparticles was studied. A significant reduction of mortality of mice was recorded after a single intraperitoneal (i. p.) injection of nanoparticle-associated Vinblastine. A wide range of doses of Vinblastine (1.04-6.25 mg/kg) were used. There was a considerable decrease of leucopenia caused by Vinblastine-loaded polybutyl-2-cyanoacrylate nanoparticles as compared to that induced by free Vinblastine.

Animals↗

PubMed1977

Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on axonal fibrillar organelles in vitro.

Axonal ultrastructural changes induced by three Vinca alkaloids, vincristine, vinblastine, and desacetyl vinblastine amide, were studied in vitro at concentrations of 0.01, 0.05, and 0.1 mM in the cat vagus nerve. Disruption of microtubules, appearance of paracrystalline structures, and increase in neurofilaments were induced by all three agents at 0.1 mM. A new type of paracrystal with an electron-dense central core in each subunit was also observed with each drug. Whereas all three compounds affected unmyelinated fibers (vinblastine more so than the other two), only vinblastine significantly damaged the myelinated fibers. The greater effectiveness of vinblastine in causing these in vitro ultrastructural changes contrasts strikingly with the clinical in vivo situation in which vincristine is the most neurotoxic. This suggests that clinical neurotoxicity is associated with additional factors aside from the direct interaction of the Vinca alkaloids with microtubules or tubulin.

Animals↗

PubMed1986

High-dose versus low-dose vinblastine in cisplatin-vinblastine-bleomycin combination chemotherapy of non-seminomatous testicular cancer: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group.

Two hundred fourteen patients with disseminated non-seminomatous testicular cancer were randomized to receive induction chemotherapy with cisplatin, vinblastine, and bleomycin (PVB). The randomization was for vinblastine 0.4 mg/kg/cycle or 0.3 mg/kg/cycle. The complete response (CR) rates to both regimens were identical: 68% and 71%, respectively. In addition, there was no significant difference in disease-free and overall survival. There was a significant decrease in the incidence of WBC nadirs below 1,000/microL: 29% and 13%, respectively (P = .01). Of the non-hematologic toxicities, there was a significant reduction in the incidence of mucositis: 53% and 37%, respectively (P = .006). The major prognostic factor was tumor volume. This study confirms that vinblastine 0.3 mg/kg/cycle in PVB chemotherapy is as effective and less toxic than vinblastine 0.4 mg/kg/cycle.

Adolescent↗

PubMed1991

A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study.

This is a Southwest Oncology Group (SWOG) prospective randomized trial of cisplatin, vinblastine, and bleomycin (PVB) versus vinblastine, cisplatin, and etoposide (VP-16) (VPV) in the treatment of advanced germ cell tumors of the testis. The study objective was to determine what effect the replacement of bleomycin with VP-16 has on complete response (CR), survival, and drug toxicity. One hundred sixty-nine patients were registered and randomized. Of these patients, 160 were assessable for response. All had histologically confirmed disseminated germ cell neoplasms of testicular origin. Forty-six had minimal metastatic disease, and 114 had maximal disease. Seventy-seven were randomized to PVB and 83 to VPV chemotherapy. There was no significant difference in pretreatment characteristics between the two arms with regard to tumor burden, histologic type, and overall performance status. Patients received four courses of induction chemotherapy, either PVB (cisplatin 120 mg/m2 day 3, vinblastine 12 mg/m2 day 1, bleomycin 15 U/m2 twice per week) or VPV (vinblastine 8 mg/m2 day 1, cisplatin 120 mg/m2 day 3, VP-16 50 mg/m2 days 2 to 5). Chemotherapy was given every 3 weeks. Cytoreductive surgery was done postinduction if a chemotherapy CR was not achieved. There was no difference in the percentage of patients achieving a disease-free status between PVB (77%) and VPV (73%). The mean leukocyte nadir was similar for both treatments, but the mean platelet nadir was significantly lower (P = .003) in the VPV arm. All bleomycin-related toxicities (pulmonary, mucositis, skin) were avoided in the VPV arm. We conclude that bleomycin can be replaced in first-line therapy for advanced germ cell tumors without sacrificing efficacy and with the advantage of avoiding unnecessary drug toxicity.

Adolescent↗

PubMed1978

Variables for predicting serious toxicity (vinblastine dose, performance status, and prior therapeutic experience): chemotherapy for metastatic testicular cancer with cis-dichlorodiammineplatinum(II), vinblastine, and bleomycin.

Combination chemotherapy utilizing high-dose vinblastine, bleomycin, and cisdichlorodiammineplatinum(II) (CDDP) is effective treatment for metastatic testicular cancer. Unfortunately, it is frequently associated with serious toxicity. In a series of 14 patients receiving 65 treatment cycles, several variables were examined as putative risk factors for prediction of serious toxicity. These included drug dose normalized to body weight or surface area, interval since previous cycle, prior therapeutic experience with either radiation therapy or other cytotoxic chemotherapy, and Karnofsky performance status. The strongest determinant of serious toxicity was the vinblastine dose calculated according to body weight. The next most influential prognostic variables were the performance status and a history of previous treatment with either radiation therapy or chemotherapy. Serious toxicity may be anticipated at a frequency of 40% when vinblastine is administered at a total dose of 0.36 mg/kg with bleomycin and CDDP. In our group of patients, the nephrotoxicity of CDDP appeared to be cumulative despite intensive diuresis at the time of administration. Pulmonary toxicity was not observed. Modest reductions in vinblastine dose, especially in patients with poor performance status or a history of previous radiation or other chemotherapy, will substantially lower the frequency of serious toxicity.

Adolescent↗

PubMed1976

Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on microtubules in vitro.

The Vinca alkaloids differ in their chemotherapeutic effectiveness and their toxicities. To determine whether differences are due to a differential effect on the assembly of tubulin into microtubules, we examined the effects of vincristine, vinblastine, and a newer alkaloid, desacetyl vinblastine amide, on the assembly of bovine brain tubulin in vitro. The three compounds block bovine tubulin polymerization in vitro and almost equally effectively at a 1 muM concentration (tubulin, 6.5 muM). At 10 muM, the three alkaloids also interact with preformed microtubules in vitro, causing spiral-like distortions of the microtubules. No effect of the alkaloids on polymerization of another fibrous protein, actin, was observed. Thus the differential actions of vinblastine, vincristine, and desacetyl vinblastine amide in vivo seems to be based on some biological process other than the reaction with tubulin or the microtubules per se.

Animals↗

PubMed1977

Cyclophosphamide, vinblastine, procarbazine and prednisone with CCNU and vinblastine maintenance for advanced Hodgkin's disease.

Fifty patients with advanced Hodgkin's disease were treated with a combination of cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) in a 21-day cyclic regimen. Thirty-one patients (62%) achieved a pathologically documented complete remission (CR). Of the 23 previously untreated patients, 13 obtained CR. Twenty-seven patients had been previously treated and 15/19 (79%) of those with prior major radiation therapy and 3/8 (37.5%) of those who had received both irradiation and chemotherapy achieved CR. Sixteen of the patients who attained CR received maintenance therapy with monthly alternating CCNU and vinblastine but as of this report, neither remission duration nor survival is significantly prolonged when compared to the 14 patients followed in remission on no therapy. Patients who received more than six courses of induction therapy (median 9.5, range 8-12) have had significantly fewer relapses and longer remissions than have those patients who received only six courses of therapy. It is concluded that: 1) CVPP is an effective regimen at inducing CR in patients with advanced Hodgkin's disease and has less gastrointestinal and neurologic toxicity than MOPP; 2) maintenance therapy with CCNU and vinblastine to date has not been beneficial; and 3) greater than six courses of induction chemotherapy prolongs remission duration and is associated with fewer disease relapses.

Adult↗

PubMed1998

A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party.

Transitional cell carcinomas may arise at any site within the urinary tract and are a source of considerable morbidity and mortality. In particular, patients with metastatic disease have a poor prognosis, with less than 5% alive at 5 years. A multicentre randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced or metastatic transitional cell carcinoma was conducted in the UK. From April 1991 to June 1995, 214 patients were entered by 16 centres, 108 randomized to CMV and 106 to MV. A total of 204 patients have died. The hazard ratio (relative risk of dying) was 0.68 (95% CI 0.51-0.90, P-value = 0.0065) in favour of CMV. This translates to an absolute improvement in 1-year survival of 13%, 16% in MV and 29% in CMV. The median survival for CMV and MV was 7 months and 4.5 months respectively. Two hundred and eight patients objectively progressed or died. The hazard ratio was 0.55 (95% CI 0.41-0.73, P-value = 0.0001) in favour of CMV. Two hundred and nine patients symptomatically progressed or died. The hazard ratio was 0.48 (95% CI 0.36-0.64, P-value = 0.0001) in favour of CMV. The most important pretreatment factors influencing overall survival were WHO performance status and extent of disease. These two factors were used to derive a prognostic index which could be used to categorize patients into three prognostic groups. We conclude that the addition of cisplatin to methotrexate and vinblastine should be considered in patients with transitional cell carcinoma, taking into account the increased toxicity.

Aged↗

PubMed1999

Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial.

PURPOSE: To compare vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: A total of 201 patients with metastatic prostate cancer, progressive after hormonal therapy and antiandrogen withdrawal (if prior antiandrogen treatment), were randomized to receive vinblastine (V) 4 mg/m(2) by intravenous bolus weekly for 6 weeks followed by 2 weeks off, either alone or together with estramustine phosphate (EM-V) 600 mg/m(2) PO days 1 through 42, repeated every 8 weeks. Of 193 eligible patients, 98 received V, and 95 received EM-V. RESULTS: Overall survival trended in favor of EM-V but was not significantly different as determined by Kaplan-Meier analysis (P =.08). Median survival was 11.9 months for EM-V and 9.2 months for V. EM-V was superior to V for secondary end points of time to progression (P <. 001, stratified log rank test; median 3.7 v 2.2 months, respectively) and for proportion of patients with >/= 50% prostate-specific antigen (PSA) decline sustained for at least 3 monthly measurements (25.2% v 3.2%, respectively; P <.0001). Granulocytopenia was significantly less for EM-V compared with V (grade 2, 3, and 4 = 7%, 7%, and 1% v 27%, 18% and 9%, respectively; P <.0001); however, grade 2 or worse nausea (26% v 7%, respectively; P =.0002) and extremity edema (22% v 8%, respectively; P =.005) were more frequent for EM-V. CONCLUSION: Although overall survival was not significantly greater for the combination, EM-V was superior to V for time to progression and PSA improvement. These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC.

Administration, Oral↗

PubMed1994

Randomized study for the treatment of adult advanced Hodgkin's disease: epirubicin, vinblastine, bleomycin, and dacarbazine (EVBD) versus mitoxantrone, vinblastine, bleomycin, and dacarbazine (MVBD).

Seventy patients with previously untreated advanced Hodgkin's disease and without bulky disease were entered in a prospective randomized clinical trial comparing epirubicin in combination with vinblastine, bleomycin, and dacarbazine (EVBD) with a regimen containing mitoxantrone, vinblastine, bleomycin, and dacarbazine (MVBD). Both groups were comparable for the variables of age, sex, stage, and presence of B symptoms and histology. Thirty-one (88%) of EVBD-treated patients achieved a pathologically documented complete remission (CR) compared to the 24 cases (68%) of the MVBD-treated group. After a median follow-up of 36 months, duration of CR is better in the EVBD-treated patients with an actuarial 5-year duration of CR of 80%, statistically different to the MVBD group: 53% (P < 0.01). Both regimens showed the same gastrointestinal toxicity, but the patients treated with the MVBD regimen shown most and severe hematological and cardiac toxicities. Also, biochemical alterations in hepatic test were observed in these patients. The alternative use of epirubicin in combination chemotherapy appears to be as effective in advanced Hodgkin's disease without bulky disease, with reduced clinical toxicity. Mitoxantrone containing regimen was not found to have an equivalent efficacy and clinical toxicity was most frequent and severe. We felt that mitoxantrone could be consider a second-line drug in the treatment of advanced Hodgkin's disease.

Actuarial Analysis↗

PubMed1994

A comparative study of cisplatin and vinblastine versus ifosfamide, cisplatin and vinblastine in non-operable non-small-cell lung cancer. A study of the Hellenic Co-operative Oncology Group for Lung Cancer Trials.

PURPOSE: To evaluate the efficacy and toxicity of ifosfamide in combination with cisplatin and vinblastine in non-operable non-small-cell lung cancer (NSCLC). METHODS: A total of 136 patients with stage III or IV NSCLC were randomized to either PV (cisplatin, 120 mg/m2, and vinblastine, 6 mg/m2) or VIP (PV with the addition of ifosfamide, 3 g/m2) every 3 weeks. RESULTS: Patients receiving VIP had a higher response rate (31% vs. 10%), but the performance status (PS) was significantly worse in those receiving PV. No difference in survival can be demonstrated between the two treatment groups. The median survival was 8.4 months. In both groups, patients with stage III disease, good PS and no visceral involvement had better survivals. Nausea/vomiting and alopecia were more pronounced in the VIP group, although both chemotherapies were well tolerated. CONCLUSIONS: The addition of ifosfamide improved the response rate, but a survival advantage cannot be proven. The prognostic value of stage, PS and metastatic site is confirmed in this trial; further studies are required to select subgroups of patients who may have a survival benefit with combination chemotherapy. The response rate elicited by VIP makes it a candidate for neoadjuvant treatment.

Adult↗

PubMed2003

Three cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or epirubicin, bleomycin, vinblastine, and methotrexate (EBVM) plus extended field radiation therapy in early and intermediate Hodgkin disease: 10-year results of a randomized trial.

From 1990 to 1996, a total of 386 adult patients with early/intermediate Hodgkin disease (HD) were randomly assigned to receive 3 cycles of adriamycin, bleomycin, vinblastine, dacarbazine (an alkylating agent), and methylprednisolone (ABVDm, arm A) or epirubicin, bleomycin, vinblastine, methotrexate, and methylprednisolone (EBVMm, arm E), a combination without alkylating agent. Responding patients received extended field radiation therapy (RT). Postchemotherapy complete remission and 10-year freedom from progression rates were higher in arm A (79.5% and 91.4%) than in arm E (70.4%, P =.04, and 80%, P <.002). HD mortality (HDM), treatment-related mortality (TRM), and overall survival (OS) were similar in both arms (A, 2.1%, 7.5%, and 90.4%; B, 3.9%, 5.5%, and 90.3%). However TRM and OS rates were lower in patients aged 40 years or older (P <.005), reflecting the increasing incidence of background fatal events with increasing age. Finally, event-free survival (EFS) was higher in arm A (84.6%) than in arm E (74.9%, P <.02). In patients aged younger than 40 years in arm A (74%), 10-year EFS and OS rates were 88.9% and 95.4% with HDM and TRM rates as low as 0.7% and 3%. Three courses of ABVDm plus RT are the best available option for treating early or intermediate HD.

Adolescent↗

PubMed1986

Vinblastine plus cisplatin in advanced non-small cell lung cancer: lack of advantage for vinblastine infusion schedule.

We have evaluated 31 patients with advanced non-small cell lung cancer treated by short-term 5-day vinblastine infusion combined with bolus cisplatin. Nine of 31 patients (29%) had partial and complete responses. Although five of nine (55%) of the responders were alive at greater than or equal to 1 year, three of the 31 patients experienced drug-related mortality. Our experience, as well as a review of previously reported trials in the literature, suggests that the infusion schedule of vinblastine offers no advantage over the bolus schedule.

Adenocarcinoma↗

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↗