Tumor progression and metastatic dissemination in ovarian cancer after dose‐dense or conventional paclitaxel and cisplatin plus bevacizumab

Abstract

The efficacy of therapeutic regimens incorporating weekly or every-3-weeks paclitaxel (PTX) for ovarian cancer is debated. We investigated the addition of bevacizumab in regimens of chemotherapy with different PTX doses and schedules in preclinical models. Treatments were cisplatin (DDP) with weekly PTX (conventional), or dose-dense-equi (every other day to the conventional cumulative dose), or dose-dense-high (total dose 1.5 times higher), with or without bevacizumab. Treatment efficacy was evaluated analyzing tumor growth in different time-windows in two patient-derived ovarian cancer xenografts with different sensitivity to cisplatin. Tumor progression, metastasis and survival were studied in ovarian cancer models growing orthotopically and disseminating in the mouse peritoneal cavity. Short-term effects on cell cycle, tumor cell proliferation/apoptosis and vasculature were evaluated by flow cytometry and immunohistochemistry. PTX dose-dense (with/without DDP) was superior to the conventional scheme in a dose-dependent manner; the high efficacy was confirmed by the lower ratio of tumor to normal cells. All schemes benefited from bevacizumab, which reduced tumor vessels. However, DDP/PTX dose-dense-high (only chemotherapy) was at least as active as DDP/PTX conventional plus bevacizumab. DDP/PTX dose-dense-high plus bevacizumab was the most effective in delaying tumor progression, though it did not prolong mouse survival and the continuous treatment with bevacizumab was associated with a malignant disease. These findings indicate that the effect of bevacizumab in combination with chemotherapy may depend on the schedule-dose of the treatment and help to explain the unclear benefits after bevacizumab.

TMEM30A deficiency in endothelial cells impairs cell proliferation and angiogenesis

“…Angiogenesis is a fundamental process in neovascularization, which plays important roles in multiple pathological conditions, such as AMD and cancer (Carmeliet and Jain, 2000). Interventions into the angiogenesis process by chemical or antibody-based drugs have been used to treat certain diseases, such as AMD and cancer (Bizzaro et al, 2018;Calugaru and Calugaru, 2018;Feng et al, 2018;Gorsi et al, 2018;Hutton-Smith et al, 2018;Martini et al, 2018). Our findings in this research have unveiled indispensable roles for TMEM30A, the β-subunit of P4-ATPases, in angiogenesis, which could provide new targets for the treatment of these diseases.…”

<p>Beyond The T/C Ratio: Old And New Anticancer Activity Scores In Vivo</p>

“…When necessary, the regrowth rate (scored for instance by a “regrowth doubling time”- Dt regrowth ) would provide additional information: if it differs from the growth rate of untreated tumors, this would prove the existence of a modification of the tumor itself or of its microenvironment. An example of the analysis of tumor growth in different time-windows was recently reported, for comparing different treatment schemes in ovarian cancer models 25…”

A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model

“…The life expectancy of patients with pleural mesothelioma is often less than 15 months. 41,42 Peritoneal dissemination is frequently caused by recurrent abdominal malignancy in patients with gastrointestinal cancer, 21,22 ovarian cancer, [43][44][45] or pancreatic cancer, [46][47][48] resulting in a poor prognosis for patients. With a great deal of continuous effort to improve the chemotherapeutic regimens, the prognosis of these advanced cancers has currently improved.…”