Death due to intrathecal vindesine.

As with vincristine, intrathecal injection of vindesine can cause fatal or irreversible neurological lesions. In addition to adopting treatment protocols designed to keep intravenous and intrathecal administration totally separate, intravenous vindesine should be used exclusively after dilution in sufficiently large infusion bags.

Complex combination biochemotherapy regimen in advanced metastatic melanoma in a non-intensive care unit: toxicity or benefit?

BACKGROUND: There is currently no chemotherapy or chemoimmunotherapy regimen that has shown impact on survival in patients with metastatic melanoma. Different biochemotherapy protocols showed promise with high response rates, but again without significant impact on survival. METHODS: We report the results of a retrospective analysis of a regimen consisting of dacarbazine, cisplatin, vindesine, interleukin-2 and interferon-alpha2b in 25 consecutively treated patients with regard to toxicity, efficacy and practicability. The treatment was performed on a regular dermatological ward. RESULTS: Grade III and IV toxicities were mainly haematological, with few cases of infection because of neutropenia seen. Best overall responses were CR 2/25, PR 2/25 and SD 9/25. The median progression free interval was 4 months (range 0-19) for all patients and the median survival time was 12 months (range 2-26). From a safety and practical point of view, there was no draw-back on treating patients in a non-intensive care unit. The median survival time is in the range of the one reported for monochemotherapy regimen. While there are some responding patients, the responses are short lived and go in parallel with high toxicity and impaired performance status. CONCLUSION: This complex and highly toxic chemoimmunotherapeutic regimen should not be considered as standard therapy in patients with metastatic malignant melanoma.

MOPPEBVCAD chemotherapy with limited and conditioned radiotherapy in advanced Hodgkin's lymphoma: 10-year results, late toxicity, and second tumors.

PURPOSE: MOPPEBVCAD (mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine) chemotherapy with limited radiotherapy was devised in 1987 to reduce late toxicity and second tumor incidence while trying to improve effectiveness through increases of dose intensity and dose density. Late results, toxicity, and second tumor incidence were reviewed in all the patients treated. EXPERIMENTAL DESIGN: The drugs of three previous alternating regimens [CAD (lomustine, melphalan, and vindesine), MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), and ABV (doxorubicin, bleomycin, and vinblastine)] were intensified and hybridized, the cumulative dose of mechlorethamine was lowered, and irradiation was delivered to no more than two sites either bulky or partially responding to chemotherapy. RESULTS: A total of 307 previously untreated advanced-stage patients underwent MOPPEBVCAD chemotherapy. Radiotherapy was delivered to 118 of 307 patients (38%). Remission was complete in 290 patients (94%). With a median follow-up of 114 months, 10-year overall, disease-free, and failure-free survival rates were 79%, 84%, and 71%, respectively. Forty-two patients relapsed and 60 died. The causes of death were Hodgkin's lymphoma in 36 patients, second neoplasms in 12, cardiorespiratory diseases in 4, pulmonary diseases in 2, and unknown in 6. Sixteen second tumors (of which nine were myelodysplasia and/or acute leukemia) were diagnosed in all. Outside this series of 307 patients, MOPPEBVCAD obtained complete responses in 12 of 15 relapsed and 9 of 9 refractory patients who had previously been treated with other regimens. CONCLUSIONS: Clinical response and long-term results are very satisfactory, whereas the second tumor incidence was lower than would have been expected with MOPP analogues. Given its response/late toxicity balance, MOPPEBVCAD does not undermine the leading role of ABVD as first-line regimen but can be indicated as a very effective second-line conventional therapy.

Olfactory epithelial lesions induced by various cancer chemotherapeutic agents in mice.

In order to examine and compare the potential toxicity in the olfactory epithelium, the antitumor drug vincristine sulfate (VCR), vinblastine sulfate(VBL), vindesine sulfate (VDS), paclitaxel (PTX), mitomycin C (MMC), 5-fluorouracil, (5-FU) or cisplatin (CDDP) was intravenously injected once(designated as day 1) at an estimated 10% lethal dose (LD(10)) to male BALB/c mice. The animals were necropsied on days 2, 5 and 15, and nasal tissues were examined by light-microscopy, counting of epithelial cells positive for terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL), immunohistochemical staining with keratin antibody, and electron microscopy. Further, to delineate the drug disposition in the target organ, whole-body radioluminography was performed 1 hour and 24 hours after treatment with the LD(10) of PTX or 5-FU. Of the antitumor drugs employed, only the antimicrotubule agents, VCR, VBL, VDS, and PTX, induced single cell death in the olfactory epithelium, especially sensory cells on day 2, atrophy of the olfactory epithelium on day 5, and myelin fragmentation in the trigeminal nerve on day 15. PTX induced the strongest changes among the 4 antimicrotubule agents. The cell death was confirmed to be apoptosis by TUNEL assay and electron microscopy, whereas the change in horizontal basal cells of the olfactory epithelium was shown not to be apoptosis by keratin staining. In quantitative radioluminography,radioactivity of PTX in the nasal tissues both 1 hour and 24 hours after administration was about 4- or 5-fold higher than those of 5-FU. These results suggest that tubulin-targeting antitumour drugs could induce apoptosis in the olfactory epithelial cells of mice and that high drug distribution may effect the onset of the olfactory lesions.

Treatment of acute lymphoblastic leukemia in the elderly: an evaluation of interferon alpha given as a single agent after complete remission.

Although interferon (IFN) has been used in elderly patients with acute lymphoblastic leukemia (ALL), the benefits from IFN therapy have not been properly assessed, especially as it was given combined with other cytotoxic drugs, which obscured the role of IFN if any. In 1997, we started a study aimed at improving our previous results in elderly patients with ALL and at assessing the therapeutic role of IFN in this disease. Fifty-eight patients with ALL, aged 55-81 years (median: 64.9 years), were randomly allocated to treatment with vindesine or vincristine during induction. After a first consolidation course, IFN was administered as a single agent for three months together with cranial radiotherapy. Chemotherapy was then resumed with a second consolidation course and maintenance. A complete remission (CR) was obtained in 58% of patients (CI: 45-71%), significantly less than in our previous study which included IFN combined with chemotherapy during maintenance (CR: 85%, CI:70-94%, p = 0.007). Overall survival (median: 289 vs 434 days in the previous study, p = 0.01) and disease-free survival (median: 146 vs 427 days, p = 0.009) were also inferior in the present study. In particular, the pattern of relapses over time suggested that the 3 month IFN treatment phase with no additional chemotherapy might have contributed to the comparatively poor outcome of this cohort. In addition, vindesine given during induction did not prove less neurotoxic than vincristine, did not improve the CR rate, and had no impact on survival. In conclusion, although similar to published studies in elderly patients with ALL, this study is inferior to our previous one. INF, given as a single drug, has a modest role if any in the treatment of older persons with ALL.

Cisplatin-based chemotherapy for postoperative recurrence in non-small cell lung cancer patients: relation of the in vitro chemosensitive test to clinical response.

The usefulness of the in vitro chemosensitivity test, the collagen gel droplet embedded culture drug- sensitivity test (CD-DST, Int J Oncol 11: 449, 1997), in cisplatin-based combined chemotherapy for postoperative recurrent tumors in non-small cell lung cancer (NSCLC) patients was retrospectively analyzed. CD-DST data for cisplatin (or carboplatin), etoposide, 5-fluorouracil, mitomycin C, and vindesine were obtained in 311 surgically resected primary lesions. Of them, 25 patients were practically treated with first-line cisplatin- or carboplatin-based chemotherapy for postoperative initial recurrence. Nine (36%) of them responded to the combined chemotherapy for recurrent lesions, including one with complete remission, whereas 16 did not, with no change in 5 and progression in 11. Seven (70%) of 10 patients receiving combined chemotherapy using two or three in vitro sensitive chemoagents showed good responses, whereas there was no responder among the patients receiving chemotherapy including no in vitro sensitive chemoagents. In particular, of 11 patients showing good sensitivity to cisplatin or carboplatin on CD-DST, 8 (73%) responded to chemotherapy, whereas only one (7%) of 14 patients showing cisplatin- or carboplatin-resistance on CD-DST was a responder. Thus, CD-DST results for the chemoagents, especially cisplatin or carboplatin, correlated with chemotherapeutic response, indicating that the CD-DST analysis of surgically resected primary NSCLC tumors is a practically useful indicator of the clinical effect of first-line cisplatin-based combined chemotherapy for postoperative recurrence.

Intensive chemotherapy (LNHIV-91 regimen) and G-CSF for HIV associated non-Hodgkin's lymphoma.

The purpose of the study was to evaluate the safety and long-term efficacy of an intensive chemotherapy regimen associated with G-CSF in HIV-associated non-Hodgkin's lymphoma (NHL). Fifty two consecutive patients with HIV infection, aggressive NHL and CD4+ cells > or = 100 x 10(6)/l were included. The median CD4 cell count was 276 x 10(6)/l. Nineteen tumors were of the Burkitt's type, 23 were large cells, 7 immunoblastic, and 3 anaplastic. Twenty-five patients had stage IV disease (bone marrow involvement in 7, and central nervous system in 9). Three cycles of ACVBP (doxorubicine, cyclophosphamide, vindesine, bleomycin, prednisolone) were given. A fourth cycle was delivered to patients in partial remission or with initial bulky disease. The induction was followed by three cycles of CVM (cyclophosphamide, etoposide, methotrexate). G-CSF 5 microg/kg was used at each cycle. Results showed that 37 patients (71%) achieved a complete remission. With a median follow-up of 74 months, 8 of them have relapsed. The median survival was 15 months and 34 patients have died (21 with NHL). The 4-year estimate survival was 33.9% (95% CI, 19.8%-47.4%). The Relative Dose-Intensity of the chemotherapy was 85% for doxorubicine and 87% for cyclophosphamide. In a multivariate analysis, homosexual men and patients with ECOG < 2 had a lower risk for death: RR = 0.32 (95% CI, 0.15-0.65) and RR = 0.36 (95% CI, 0.18-0.74), respectively. Achievement of complete remission was strongly associated with survival. In conclusion, it seems that in HIV-infected patients with NHL and a CD4 cell count above 100 x 10(6)/l, high complete remission rate and prolonged survival can be achieved with the intensive LNHIV-91 regimen.

Lomustine and melphalan cannot be replaced by cyclophosphamide and etoposide without reducing efficacy in MOPPEBVCAD chemotherapy for advanced Hodgkin's disease.

BACKGROUND AND OBJECTIVES: To evaluate the feasibility, toxicity and preliminary results of a potentially less toxic variant of the MOPPEBVCAD chemotherapy regimen for advanced Hodgkin's disease: MOPPEBVCyED, in which cyclophosphamide and etoposide replace lomustine and melphalan, respectively, with the remaining components being unaltered. DESIGN AND METHODS: The study was multicenter, prospective and randomized, and enrolled 67 patients with newly diagnosed stage IIB, III, IV Hodgkin's disease (62 were expected on the grounds of statistical considerations). Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. Median follow-up was 48 months. RESULTS: Comparing MOPPEBVCAD vs. MOPPEBVCyED, the results were as follows: complete remissions 35/35 vs. 30/32 (plus one partial remission and one disease progression); relapses 5 vs. 8; deaths 2 (one of myelodysplasia) vs. 2; delivered mean dose intensity (DI): lomustine 0.79+/-0.67 vs. cyclophosphamide 0.82+/-0.32; melphalan 0.80+/-0.13 vs. etoposide 0.86+/-0.18; average DI of the 7 drugs common to both regimens 0.73+/-0.10 vs. 0.83+/-0.11; all 9 drugs 0.75+/-0.13 vs. 0.84+/-0.09 (p=0.002); projected 5-year failure-free survival 0.79 vs 0.62; second cancers, two myelodysplasias vs. one carcinoma of the kidney. Toxicities were not statistically different except for heavier thrombocytopenia being recorded with MOPPEBVCAD. INTERPRETATION AND CONCLUSIONS: The higher cumulative and single drug DI recorded with MOPPEBVCyED may reflect better short-term tolerability, but it does not lead to better disease control. Its late toxicity may be expected to be lower in the future but at present it does not seem to be a sufficient reason to substitute MOPPEBVCyED for MOPPEBVCAD.

OPP-EBV-CAD regimen as salvage treatment in advanced refractory or resistant multiple myeloma.

With the aim of developing an effective therapy for heavily pretreated refractory MM outpatients, we evaluated the OPPEBVCAD regimen, a Hodgkin's disease-derived protocol that includes many drugs effective in MM administered in a sequential schedule. Twenty-two pts aged 42-72 years, with symptomatic highly-pretreated refractory (18 cases), or primary resistant MM (four cases. including two pts with plasma cell leukemia-PCL) received this therapy every 28 days (2-4 cycles, followed by a maintenance program). Therapeutic response (Chronic Leukemia-Myeloma Task Force criteria) and performance status (PS) and pain (W.H.O.) were evaluated. All of the pts were evaluable for response. There were 9 (40%) objective responses (OR: stabilization of blood counts and bone lesions, serum calcium normalization, 50% or more reduction in the concentration of serum monoclonal component (MC), 90% reduction in Bence-Jones proteinuria), 8 (36%) partial responses (PR: 25-50% reduction in serum MC), 1 no response or stable disease (NR), and 4 (18%) cases of progressive disease (PD). OR plus PR were 77%. Of the 4 primary resistant tumors (2 PCL and 2 MM), 2 achieved PR, 1 OR (a PCL case) and 1 progressed. Median survival was 15 months for responding pts (OR plus PR) and 4.5 months for non-responders (NR plus PD). PS and pain improved in 15 pts and did not change in 9. The most frequent side effects were cytopenias, with one drug related infective death. The OPPEBVCAD regimen proved to be an effective therapy for refractory relapsing or primary resistant MM: in responders (two-thirds of the pts), survival was prolonged by about 10 months. Its efficacy in anthracycline-treated pts, as well as the feasibility of using it on an outpatient basis without any continuous drug infusions, make this regimen a promising third line salvage therapy.

Carboplatin, vindesine, 5-fluorouracil-leucovorin and 13-cis retinoic acid in the treatment of advanced non-small cell lung cancer. A phase II study.

PURPOSE: Carboplatin, vindesine and 5-fluorouracil/leucovorin are drugs active in the treatment of non-small cell lung cancer (NSCLC) and they can be administered in an outpatient setting. Retinoids, which are widely used agents in chemoprevention, have been reported to exert (in vitro models) growth inhibitory effects of synergistic type with chemotherapy, and differentiating effects on NSCLC cells. PATIENTS AND METHODS: 28 patients with advanced NSCLC with measurable disease were entered into the trial. Eligibility criteria included performance status < or = 3 and adequate renal and liver function. Patients with brain metastases were not excluded. Treatment was as follows: Carboplatin (CBCDA) 300 mg/m2 day 1, Vindesine (VDS) 3 mg/m2 days 1 and 5, leucovorin (L) 100 mg/m2, 5-fluorouracil (5-FU) 370 mg/m2 for 5 days and 13-cis retinoic acid (R) 1 mg/kg, administered between chemotherapy courses. After 6 courses of chemotherapy responders were maintained with R, until progression. RESULTS: 120 courses of chemotherapy have been delivered (median 4 courses per patient, range 1 to 6). All patients were evaluable for response and toxicity. Objective responses: 2 complete responses (CR) (7%), 9 partial responses (PR) (32%), 9 stable disease (SD) (32%), 8 progressive disease (PD) (29%). (Response rate 39%, 95% CI: 22% to 60%). Median time to progression was 7.7 months (range 3.4-22) and median survival was 9.7 months (range 0.5-27) with 40% of patients alive after one year. Toxicity WHO: hematological grade 3-4 in 46% of patients, grade 2 diarrhea in 21% of patients, ileus in 14% of patients, Neurologic grade 2 in 11% of patients. CONCLUSIONS: The addition of RA to CBDCA, VDS, FU, L, R represents an effective treatment in NSCLC, with manageable toxicity.

High-dose methotrexate and HELP [Holoxan (ifosfamide), eldesine (vindesine), platinum]--doxorubicin in non-metastatic osteosarcoma of the extremity: a French multicentre pilot study. Fédération Nationale des Centres de Lutte contre le Cancer and Société Française d'Oncologie Pédiatrique.

UNLABELLED: This study evaluates histological response, long-term outcome, and toxicity in an intensive chemotherapy program given before surgery. PATIENTS AND METHODS: Sixty-two patients (39 males, 23 females: median age 14) with biopsy, chest computerised-tomography, technetium bone-scan and magnetic resonance imaging, were enrolled. Primary localisations were femur (44%) and tibia (26%). Induction chemotherapy involved seven courses of high-dose methotrexate and two courses of HELP (ifosfamide, eldesine (vindesine), cisplatin (platinum)-doxorubicin. After surgery, patients received six courses of high-dose methotrexate and two courses of HELP-doxorubicin. RESULTS: Pre- and postoperative toxicities were similar. Fifty-nine patients underwent surgery; histological response was good in thirty-eight patients (64%) and poor in twenty-one (36%). Median follow-up is 57 months (range 30-80), with 77% overall survival and 59% progression-free survival. In a multivariate analysis, age under 10 years is the only prognostic factor that significantly correlates with outcome. CONCLUSIONS: This regimen appears to increase histological necrosis, but associates with severe toxicity. Results for patients with less necrosis at surgery are encouraging. Future trials should determine the minimum effective doses to reduce toxicity. New drugs should be added.

Induction chemotherapy employing dose-intense cisplatin with mitomycin and vinblastine (MVP400), followed by thoracic surgery or irradiation, for patients with stage III nonsmall cell lung carcinoma.

BACKGROUND: Cisplatin-based induction chemotherapy before surgery or irradiation has improved the survival of patients with Stage III nonsmall cell lung carcinoma (NSCLC). Encouraged by earlier results with preoperative MVP (cisplatin [120 mg/m(2) or 25 mg/m(2)/week], vinblastine, and mitomycin) for Stage IIIA patients with clinically apparent mediastinal (N2) disease, the authors conducted a Phase II trial of the safety and efficacy of induction MVP400 with the dose intensity of cisplatin doubled from 25 to 50 mg/m(2) per week. METHODS: From October 1992 to March 1996, 37 patients with Stage IIIA (26) or Stage IIIB (11) NSCLC began the MVP400 induction chemotherapy program. Four doses of cisplatin (100 mg/m(2)), 7 doses of vinblastine, and 2 doses of mitomycin were given over 9 weeks. Patients received either surgery or irradiation after induction treatment. RESULTS: Overall, the response rate was 65% (95% confidence interval, 49-81%) with a complete resection rate of 67%. The median survival was 17 months, with 66% of patients alive at 1 year. Complete resection and Stage IIIA involvement were favorable prognostic indicators for survival. No Stage IIIB patients underwent a complete resection. Myelosuppression was the most common side effect. There were no treatment-related deaths. CONCLUSIONS: Although high response and complete resection rates were again demonstrated, results with the MVP400 regimen were not improved over those achieved with MVP regimen tested earlier with Stage IIIA (N2) patients. The authors continue to recommend MVP as an induction chemotherapy regimen for clinical trials.

Expression of DNA repair proteins hMSH2, hMSH6, hMLH1, O6-methylguanine-DNA methyltransferase and N-methylpurine-DNA glycosylase in melanoma cells with acquired drug resistance.

Malignant melanoma is well known for its primary unresponsiveness to chemotherapy. The mechanisms conferring this intrinsic resistance are unclear. In this study, we investigated the role of genes involved in DNA repair in a panel of human melanoma cell variants exhibiting low and high levels of resistance to 4 commonly used drugs in melanoma treatment, i.e., vindesine, etoposide, fotemustine and cisplatin. We show that in melanoma cells exhibiting resistance to cisplatin, etoposide and vindesine, the nuclear content of each of the DNA mismatch repair (MMR) proteins hMLH1, hMSH2 and hMSH6 was reduced by 30-70%. A decreased expression level of up to 80% of mRNAs encoding hMLH1 and hMSH2 was observed in drug-resistant melanoma cells selected for cisplatin, etoposide and fotemustine, while vindesine-selected cells showed only moderate reduction. In melanoma cells that acquired resistance to fotemustine, the amount of nuclear MMR proteins was nearly unaltered, whereas the activity of O6-methylguanine-DNA methyltransferase (MGMT) was considerably enhanced. Activity of N-methylpurine-DNA glycosylase (MPG) was not significantly altered in any of the drug-resistant melanoma cells. Our data indicate that modulation of both MMR components and MGMT expression level may contribute to the drug-resistant phenotype of melanoma cells.

Influence of vindesine exposure on the micronucleus formation and cell survival in V79 cells.

Effect of different concentrations (0, 1, 5, 10, 20 and 50 nM) of vindesine sulphate was studied on clonogenicity and micronucleus (MN) formation in V79 (Chinese hamster lung fibroblasts) cells. Exposure of V79 cells to vindesine for 6 h resulted in a concentration dependent decline in cell survival. The frequency of micronuclei (MN) increased in a concentration dependent manner at 16, 22 and 28 h post-exposure. The frequency of MN increased significantly after 5 to 50 nM drug exposure at 16 and 22 h post-treatment, while increasing post-exposure time to 28 h resulted in a significant increase in MN frequency at all exposure doses of vindesine. The statistical evaluation of concurrent concentrations at various time periods showed a non-significant difference in MN frequency among various post-exposure time periods, except 16 h and 28 h for 50 nM, where a significant decline in the MN frequency was observed at 28 h compared to 16 h post-exposure. The cell proliferation indices showed a concentration dependent decline in the frequency of binucleate cells and this decline was linear quadratic. The increasing drug concentration resulted in a concentration dependent decline in cell survival. While the frequency of micronuclei increased the cell survival decreased and the relationship between cell survival and micronucleus induction was linear quadratic.

Feasibility, toxicity, and activity of LNH84-derived chemotherapy in the management of aggressive lymphomas.

The results of chemotherapy remain unsatisfactory for many patients with advanced lymphomas. Both standard and more aggressive chemotherapy regimens might have their respective role in the management of theses diseases. We have tested the feasibility and assessed the toxicity and activity of a LNH84-derived chemotherapy for aggressive non-Hodgkin's lymphoma in two general hospitals. Thirty-three untreated patients were included over a period of 4 years. Median age was 39 years, 21 were male. International Working Formulation was F for 2 patients, G for 17, H for 8, I for 1, J for 4, one unclassified. Seventeen patients had B symptoms, 15 stage IV, 8 bulky disease, 21 abnormal LDH, 5 performance status > or =2. The overall response rate was 93%. The single treatment related death resulted from bleomycin acute pneumonitis. Neutropenia WHO grade 4 occurred in all patients, resulting in infections grade 3 in 12 and thrombocytopenia grade 4 in 3. In the induction phase, courses could never be repeated day 14. The dose intensity of the four drugs contained in this phase is thus calculated between 64.5 and 81.5%. At 3 years, overall survival is 80% and event-free survival is 62%. This LNH84-derived regimen is effective. However, the induction phase is toxic and a 3-weekly interval appears more appropriate. Such intensive treatment might benefit patients with very aggressive lymphomas and this should be studied in randomized comparison against standard CHOP.

Disruptions of the hypothalamo-pituitary-adrenal axis increase anticancer drug lethality in the rat.

We have previously shown that toxicity of the anticancer agent hydroxyurea (HU) in the rat is markedly increased by hypophysectomy or adrenalectomy. In this study, we investigated whether increased toxicity in ablated animals is a unique feature of HU or it is shared with other anticancer agents; the toxic effects of five such drugs have been compared in intact, hypophysectomized (HYX) and adrenalectomized (ADX) rats. Bis-chloroethyl-nitrosourea (BCNU, 5-10 mg/kg), busulfan (0.1-10 mg/kg), cyclophosphamide (25-125 mg/kg), 5-fluorouracil (15-75 mg/kg) and vindesine (0.1-0.5 mg/kg) were given to intact and endocrine-ablated rats, and lethality was recorded over 3 weeks. It was found that mortality was low or absent in intact rats, whereas (with the exception of HYX rats receiving the highest dose of busulfan) it was dramatically increased by both hypophysectomy and adrenalectomy. However, replacement treatments with long-acting tetracosactrin and corticosterone to HYX and ADX rats respectively afforded significant protection against BCNU toxicity only. We conclude that the integrity of the hypothalamo-pituitary-adrenal axis is needed to tolerate the toxicity of various anticancer drugs, although complex mechanisms appear to underlie such protective effect.

Enhancement of micronuclei frequency by vindesine in mouse bone marrow.

Treatment of mice with various doses (0, 0.25, 0.5, 1.0 and 2.0 mg/kg b.wt.) of vindesine resulted in a dose-dependent increase in the frequency of micronucleated polychromatic erythrocytes (MPCE) and micronucleated normochromatic erythrocytes. Conversely, the polychromatic erythrocyte and normochromatic erythrocyte (P/N ratio) ratio declined with increasing dose of vindesine. The dose effect relationship for MPCE, MNCE and P/N ratio was linear quadratic.

Human melanoma cell lines selected in vitro displaying various levels of drug resistance against cisplatin, fotemustine, vindesine or etoposide: modulation of proto-oncogene expression.

Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms involved are largely unknown. In order to establish a reproducable model system for studying the exact mechanisms conferring chemoresistance, we selected drug-resistant sublines in vitro derived from one parental human melanoma (MeWo) cell line. Four commonly used chemotherapeutic drugs (vindesine, etoposide, fotemustine, cisplatin) with different modes of action were choosen and stable sublines exhibiting four different levels of resistance against each drug were selected by continuous exposure over two years. Analysis of the drug-resistant sublines regarding their pharmacological characteristics and cross-resistance pattern revealed an up to 26-fold increased relative resistance against the alkylating agent fotemustine (MeWoFOTE) and an up to 35.7-fold increased relative resistance against topoisomerase-II-inhibiting etoposide (MeWoETO). Cisplatin selection (MeWoCIS) resulted in a 6-fold higher resistance compared to parental MeWo cells, whereas vindesine exposure (MeWoVIND) increased relative resistance up to 10.2-fold. Sublines selected separately for resistance to the DNA-damaging agents fotemustine, cisplatin and etoposide demonstrated strong cross-resistance. In comparison to the parental cell line drug-resistant sublines showed altered expression patterns of proto-oncogenes. Levels of p53 mRNA decreased with increasing resistance to vindesine, etoposide and fotemustine. Expression of bcl-2 family members (bax, bcl-x) was modulated by fotemustine, etoposide and cisplatin. In addition the expression of members of the fos (c-fos) and jun (c-jun, jun-D) gene family encoding transcription factors of the AP-1 complex was altered in all drug-resistant sublines. The pattern of expression varied with the inducing stimulus and this was paralleled by changes in the transactivation potential of AP-1. Our results reinforce the central role of AP-l in drug resistance probably through its participation in a programmed cellular stress response.

Grouping of anticancer drugs based on administration method-related toxicity patterns in rats.

As part of the study of the appropriate usage of anticancer drugs, and the effects of the administration method (single dose, or divided doses) on the death rate from toxicity, five anticancer drugs (nimustine hydrochloride = ACNU, cyclophosphamide = CY, carboplatine = CBDCA, mitomycin C = MMC, vindesine = VDS) were studied in F-344 rats. A reduced death rate from toxicity was achieved by divided-dose administration of ACNU and CBDCA (group 1), but it was higher for CY and VDS (group 2), and there was no significant difference with MMC (group 3). In conclusion, the drugs were divided into three groups according to the administration method-related toxicity patterns. Improved knowledge of the properties of anticancer drugs is important for the success of chemotherapy.

Flow cytometric evaluation of the effect of various doses of vindesine sulphate on mouse spermatogenesis.

Spermatogenesis, a rapidly proliferating cell system, is highly susceptible to damage by radiotherapy and/or chemotherapy. Vindesine, a semisynthetic vinca alkaloid, was given as a single injection to adult male Swiss albino mice to study its effects on testicular weight and male germ cell turnover pattern using flow cytometry. Testicular weight declined significantly at Day 7 to 14 and from Day 14 to 35 after administration of 1 and 2 mg/kg b wt vindesine, respectively. Flow cytometric evaluation of various testicular cell types after the administration of 2 mg/kg b wt vindesine revealed a significant increase in the relative percentage of spermatogonial cells at Day 21 and 35 posttreatment. In contrast, the relative percentage of primary spermatocytes declined significantly at Day 7 and 14 posttreatment. Similarly, a significant reduction in the relative percentage of round spermatids was observed from Day 7 to 35 posttreatment. The relative percentage of elongated spermatids declined significantly at day 35 post-treatment. These changes are reflected in the transformation ratios. While the 4C:2C ratio did not exhibit any significant change below 1 mg/kg vindesine, it declined significantly after 1 mg/kg (Day 14) and 2 mg/kg (Day 7 to 35, except Day 28 posttreatment) vindesine treatment. Treatment of male mice with 2 mg/kg vindesine resulted in a significant decline in 1C:2C ratio from 7 to 35 d post-treatment. The 4C:S-phase ratio decreased significantly at Day 7 and 14 posttreatment for all the drug doses above 0.05 mg/kg. A significant reduction in the 1C:4C ratio was observed at day 21 to 35 posttreatment as a result of 2 mg/kg vindesine administration.