Vinca alkaloids: Anti-vascular effects in a murine tumour

doi:10.1016/0959-8049(93)90082-Q

European Journal of Cancer

Volume 29, Issue 9, 1993, Pages 1320-1324

https://doi.org/10.1016/0959-8049(93)90082-Q Get rights and content

Abstract

We have investigated the blood flow modifying effects of the vinca alkaloids, vincristine and vinblastine in the murine carcinoma CaNT. Vinblastine at doses of 7.5 or 10 mg/kg induced profound and chronic reductions in tumour blood flow as measured by ⁸⁶RbCl extraction. Following the maximum tolerated dose of 10 mg/kg, blood flow was reduced to 10% of pretreatment values after 2 h and remained below 20% of pretreatment values 24 h after drug administration. These findings are consistent with the early induction of necrosis by vinblastine and suggest that vascular-mediated cell death may account for a large part of the 11 day growth delay induced by this drug dose. In contrast to the large reductions in tumour blood flow, in skin, kidney, liver and muscle, blood flow reductions did not, at any time examined, exceed 40%. In all the normal tissues studied, blood flow had fully recovered by 6 h after vinblastine administration. Similar results, albeit less pronounced, have been obtained with vincristine at the maximum tolerated dose of 3 mg/kg. The results clearly show that both vinblastine and vincristine can induce, with some selectivity, a dramatic and prolonged reduction in tumour blood flow and that this may contribute to the anti-tumour effects against the CaNT tumour.

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In this work, a series of cyclic bridged analogs of isocombretastatin A-4 (isoCA-4) with phenyl or pyridine linkers were designed and synthesized. The synthesis of the desired analogs was performed by the formation of nitro-vinyl intermediates, followed by a Cadogan cyclization. Structure activity relationship (SAR) study demonstrates the critical role of the combination of quinaldine as ring A, pyridine as the linker, and indole as ring B in the same molecule, for the cytotoxic activity. Among all tested compounds, compound 42 showed the highest antiproliferative activity against a panel of cancer cell lines with average IC50 values of 5.6 nM. Also, compound 42 showed high antiproliferative activity against the MDR1-overexpressing K562R cell line; thus, it was 1.5- and 12-fold more active than the reference compounds, isoCA-4 and CA-4, respectively. Moreover, 42 displayed a strong antiproliferative activity against the colon-carcinoma cells (HT-29), which are resistant to combretastatin A-4 and isoCA-4, and it was found to be 8000-fold more active than natural CA-4. Compound 42 also effectively inhibited tubulin polymerization both in vitro and in cells, and induced cell cycle arrest in G2/M phase. Next, we demonstrated that compound 42 dose-dependently caused caspase-induced apoptosis of K562 cells through mitochondrial dysfunction. Finally, we evaluated the effect of compound 42 in human no cancer cells compared to the reference compound. We demonstrated that 42 was 73 times less cytotoxic than isoCA-4 in quiescent peripheral blood lymphocytes (PBLs). In summary, these results suggest that compound 42 represents a promising tubulin inhibitor worthy of further investigation.
Discovery of tertiary amide derivatives incorporating benzothiazole moiety as anti-gastric cancer agents in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway
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On the basis and continuation of our previous studies on anti-tubulin and anti-gastric cancer agents, novel tertiary amide derivatives incorporating benzothiazole moiety were synthesized and the antiproliferative activity was studied in vitro. Preliminary structure activity relationships (SARs) were explored according to the in vitro antiproliferative activity results. Some of compounds could significantly inhibit the proliferation of three cancer cells (HCT-116, MGC-803 and PC-3 cells) and compound F10 exhibited excellent antiproliferative activity against HCT-116 cells (IC₅₀ = 0.182 μM), MGC-803 cells (IC₅₀ = 0.035 μM), PC-3 cells(IC₅₀ = 2.11 μM) and SGC-7901 cells (IC₅₀ = 0.049 μM). Compound F10 effectively inhibited tubulin polymerization (IC₅₀ = 1.9 μM) and bound to colchicine binding site of tubulin. Molecular docking results suggested compound F10 could bind tightly into the colchicine binding site of β-tubulin. Moreover, compound F10 could regulate the Hippo/YAP signaling pathway. Compound F10 activated Hippo signaling pathway from its very beginning MST1/2, as the result of Hippo cascade activation YAP were inhibited. And then it led to a decrease of c-Myc and Bcl-2 expression. Further molecular experiments showed that compound F10 arrested at G2/M phase, inhibited cell colony formatting and induced extrinsic and intrinsic apoptosis in MGC-803 and SGC-7901 cells. Collectively, compound F10 was the first to be reported as a new anticancer agent in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway.
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Citation Excerpt :
MTAs were originally thought to act mainly through mitotic spindle disruption and subsequent apoptosis induction. Hill et al. demonstrated that vinca alkaloids dramatically decrease blood flow through tumors followed by necrosis of tumor tissue (Hill et al., 1993). The underlying mechanism involves disruption of the tumor endothelial cell cytoskeleton and junctions between endothelial cells.
Microtubule-targeting agents (MTAs) constitute a diverse group of chemical compounds that bind to microtubules and affect their properties and function. Disruption of microtubules induces various cellular responses often leading to cell cycle arrest or cell death, the most common effect of MTAs. MTAs have found a plethora of practical applications in weed control, as fungicides and antiparasitics, and particularly in cancer treatment. Here we summarize the current knowledge of MTAs, the mechanisms of action and their role in cancer treatment. We further outline the potential use of MTAs in anti-metastatic therapy based on inhibition of cancer cell migration and invasiveness. The two main problems associated with cancer therapy by MTAs are high systemic toxicity and development of resistance. Toxic side effects of MTAs can be, at least partly, eliminated by conjugation of the drugs with various carriers. Moreover, some of the novel MTAs overcome the resistance mediated by both multidrug resistance transporters as well as overexpression of specific β-tubulin types. In anti-metastatic therapy, MTAs should be combined with other drugs to target all modes of cancer cell invasion.
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A series of forty-six 5,6-annulated 2-arylthieno [2,3-d]pyrimidin-4(3H)-ones were prepared as potentially pleiotropic anticancer drugs with variance in the tubulin-binding trimethoxyphenyl motif at C-2 of a thieno [2,3-d]pyrimidine fragment, enlarged by additional rings of different size and substitution. By assessing their cytotoxicity against various cancer cells, their influence on the polymerization of neat tubulin and the dynamics of microtubule and F-actin cytoskeletons, and their vascular-disrupting and anti-angiogenic activities in vitro and in vivo, structure-activity relations were identified which suggest the 3-iodo-4,5-dimethoxyphenyl substituted thienopyrimidine 2e as a promising anticancer drug candidate for further research. 2020 Elsevier Ltd. All rights reserved.
Discovery of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives as novel tubulin polymerization inhibitors for treatment of cancer
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A new series of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives were designed, synthesized and demonstrated to act as tubulin polymerization inhibitors. These new derivatives showed significant antitumor activities, among which SKLB0533 demonstrated to be the most potent compound, with IC₅₀ values ranging from 44.5 to 135.5 nM against seven colorectal carcinoma (CRC) cell lines. Remarkably, SKLB0533 exhibited no activity against other potential targets, such as 420 kinases and EZH2. Besides, SKLB0533 inhibited tubulin polymerization, arrested the cell cycle at the G2/M phase and induced apoptosis in CRC cells. Furthermore, SKLB0533 suppressed tumour growth in the HCT116 xenograft model without inducing notable major organ-related toxicity, suggesting that SKLB0533 could be used as a promising lead compound for the development of new antitumor agents.
Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial
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For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma.
RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m² on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m², on days 1–28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing.
Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4–89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6–83·2) with maintenance chemotherapy versus 69·8% (62·2–76·2) without maintenance chemotherapy (hazard ratio [HR] 0·68 [95% CI 0·45–1·02]; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2–90·9) with maintenance chemotherapy versus 73·7% (65·8–80·1) without (HR 0·52 [95% CI 0·32–0·86]; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3–4 leucopenia, 148 (82%) had grade 3–4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved.
Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials.
Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK.

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European Journal of Cancer

Abstract

References (24)

Vascular occlusion and tumour cell death

Eur J Cancer Clin Oncol

Vascular collapse after flavone acetic acid: a possible mechanism of its antitumour action

Eur J Cancer Clin Oncol

Inhibition of growth of colon 38 adenocarcinoma by vinblastine and colchicine: Evidence for a vascular mechanism

Eur J Cancer

Flavone acetic acid (NSC 347512) induces haemorrhagic necrosis of mouse colon 26 and 38 tumours

Eur J Cancer Clin Oncol

Clinical applications of tumour necrosis factor

Prog Growth Factor Res

The effect of therapy on tumour vascular function

Int J Radiat Biol

Effect of local hyperthermia on blood flow and microenvironment

Cancer Res (Suppl.)

Destruction of rat mammary tumour and normal tissue microcirculation by hematoporphyrin derivative photoradiation observed in vivo in sandwich observation chambers

Cancer Res

Toxic effect of tumour necrosis factor on tumour vasculature in mice

Cancer Res

³¹P-NMR studies of the effect of recombinant human interleukin-1α on the bioenergetics of RIF-1 tumors

Cancer Res

Flavone acetic acid (NSC 347512)-induced modulation of murine tumor physiology monitored by in vivo nuclear magnetic resonance spectroscopy

Cancer Res

Reduction of tumor blood flow by flavone acetic acid: a possible component of therapy

J Natl Cancer Inst

Cited by (166)

Cyclic bridged analogs of isoCA-4: Design, synthesis and biological evaluation

Discovery of tertiary amide derivatives incorporating benzothiazole moiety as anti-gastric cancer agents in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway

Microtubule-targeting agents and their impact on cancer treatment

Synthesis and bioevaluation of new vascular-targeting and anti-angiogenic thieno[2,3-d]pyrimidin-4(3H)-ones

Discovery of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives as novel tubulin polymerization inhibitors for treatment of cancer

Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial

PaperVinca alkaloids: Anti-vascular effects in a murine tumour

Abstract

Eur J Cancer Clin Oncol

Eur J Cancer Clin Oncol

Eur J Cancer

Eur J Cancer Clin Oncol

Prog Growth Factor Res

The effect of therapy on tumour vascular function

Int J Radiat Biol

Effect of local hyperthermia on blood flow and microenvironment

Cancer Res (Suppl.)

Destruction of rat mammary tumour and normal tissue microcirculation by hematoporphyrin derivative photoradiation observed in vivo in sandwich observation chambers

Cancer Res

Toxic effect of tumour necrosis factor on tumour vasculature in mice

Cancer Res

31P-NMR studies of the effect of recombinant human interleukin-1α on the bioenergetics of RIF-1 tumors

Cancer Res

Flavone acetic acid (NSC 347512)-induced modulation of murine tumor physiology monitored by in vivo nuclear magnetic resonance spectroscopy

Cancer Res

Reduction of tumor blood flow by flavone acetic acid: a possible component of therapy

J Natl Cancer Inst

Paper
Vinca alkaloids: Anti-vascular effects in a murine tumour

³¹P-NMR studies of the effect of recombinant human interleukin-1α on the bioenergetics of RIF-1 tumors