Chemotherapy counteracts metastatic dissemination induced by antiangiogenic treatment in mice
Alessandra Rovida1, Vittoria Castiglioni, Alessandra Decio
1Corresponding Author: Raffaella Giavazzi, Laboratory of Biology and Treatment of Metastasis, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy. raffaella.giavazzi@marionegri.it.
Abstract:
The development of resistance and progressive disease after treatment with angiogenesis inhibitors is becoming a controversial issue. We investigated the experimental conditions that cause multireceptor tyrosine kinase inhibitors (RTKI) to augment metastasis and whether opportune combinations with chemotherapy could counteract this effect. The renal Renca-luc tumor was transplanted orthotopically in the kidney of Balb/c mice, which then were or were not nephrectomized. The Lewis Lung carcinoma (LLC) was transplanted in the tibial muscle of C57/Bl6 mice. Treatment with the RTKI sunitinib started at different stages of tumor progression, mimicking neoadjuvant or adjuvant settings. Combination studies with paclitaxel, doxorubicin, cisplatin, gemcitabine, and topotecan were done on the LLC model, using opportune regimens. In a neoadjuvant setting, sunitinib inhibited Renca-luc tumor growth, prolonging survival despite an increase in lung metastasis; treatment after primary tumor surgery (adjuvant setting) or on established metastasis prolonged survival and decreased metastasis. Sunitinib increased lung metastasis from mice bearing early-stage LLC, but did not affect established metastases (no acceleration) from advanced tumors. Combinations with doxorubicin, topotecan, gemcitabine, but not cisplatin and paclitaxel, counteracted the increase in metastasis from LLC, partly reflecting their antitumor activity. Histology analysis after sunitinib confirmed tumor vascular changes and increased hypoxia. Topotecan at suboptimal daily doses reduced sunitinib-related metastasis, reducing tumor hypoxia. Tyrosine kinase inhibitors, as sunitinib, can have adverse malignant effects mainly in the neoadjuvant setting. The addition of chemotherapy might influence metastasis, depending on each drug mechanism of action and its regimen of administration.
Insights
Multireceptor tyrosine kinase inhibitors (RTKI) like sunitinib can promote metastasis, especially before surgery. Combining RTKIs with certain chemotherapies, like doxorubicin or topotecan, may counteract this adverse effect.
Area of Science:
- Oncology
- Pharmacology
- Cancer Metastasis Research
Background:
- Angiogenesis inhibitors are crucial cancer treatments, but resistance and disease progression pose challenges.
- The potential for multireceptor tyrosine kinase inhibitors (RTKI) to unexpectedly enhance metastasis is a growing concern.
- Understanding the conditions under which RTKIs promote metastasis is vital for optimizing cancer therapy.
Purpose of the Study:
- To investigate experimental conditions causing RTKIs to augment tumor metastasis.
- To determine if combining RTKIs with chemotherapy can counteract pro-metastatic effects.
- To evaluate the impact of RTKI administration timing (neoadjuvant vs. adjuvant) on metastasis.
Main Methods:
- Orthotopic renal (Renca-luc) and tibial muscle (Lewis Lung carcinoma) tumor models in mice.
- Treatment with RTKI sunitinib in neoadjuvant, adjuvant, and established metastasis settings.
- Combination studies with various chemotherapeutic agents (paclitaxel, doxorubicin, cisplatin, gemcitabine, topotecan).
- Histological analysis to assess tumor vascularity and hypoxia.
Main Results:
- Sunitinib inhibited primary tumor growth but increased lung metastasis in the neoadjuvant setting.
- Adjuvant sunitinib or treatment on established metastasis improved survival and reduced metastasis.
- Sunitinib increased metastasis in early-stage Lewis Lung carcinoma but not in advanced tumors.
- Doxorubicin, topotecan, and gemcitabine combinations counteracted sunitinib-induced metastasis; cisplatin and paclitaxel did not.
- Topotecan reduced sunitinib-related metastasis and tumor hypoxia.
Conclusions:
- RTKIs, such as sunitinib, can exert adverse pro-metastatic effects, particularly in the neoadjuvant setting.
- The efficacy of chemotherapy combinations in mitigating RTKI-induced metastasis depends on the specific drug and administration regimen.
- Targeting tumor hypoxia with agents like topotecan may be a strategy to reduce RTKI-associated metastasis.
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