Abstract
Resistance formation of tumors against chemotherapeutics is the major obstacle in clinical cancer therapy. Although low molecular weight heparin (LMWH) is an important component in oncology referring to guideline-based antithrombotic prophylaxis of tumor patients, a potential interference of LMWH with chemoresistance is unknown. We have recently shown that LMWH reverses the cisplatin resistance of A2780cis human ovarian cancer cells in vitro. Here we address the question whether this LMWH effect is also valid under in vivo conditions. Therefore, we established tumor xenografts of A2780 and cisplatin resistant A2780cis cells in nude mice and investigated the impact of daily tinzaparin applications (10 mg/kg BW) on anti-tumor activity of cisplatin (6 mg/kg BW, weekly) considering the tumor growth kinetics. Intratumoral platinum accumulation was detected by GF-AAS. Xenografts of A2780 and A2780cis cells strongly differed in cisplatin sensitivity. As an overall consideration, tinzaparin co-treatment affected the response to cisplatin of A2780cis, but not A2780 tumors in the later experimental time range. A subgroup analysis confirmed that initially smaller A2780cis tumors benefit from tinzaparin, but also small A2780 xenografts. Tinzaparin did not affect cisplatin accumulation in A2780cis xenografts, but strongly increased the platinum content in A2780, obviously related to morphological differences in both xenografts. Although we cannot directly confirm a return of A2780cis cisplatin resistance by tinzaparin, as shown in vitro, the present findings give reason to discuss heparin effects on cytostatic drug efficiency for small tumors and warrants further investigation.
Highlights
Cancer-associated thrombosis is an important mortality factor in malignant tumor diseases [1].antithrombotic prophylaxis or treatment is a common component in the therapeutic regimes of patients with malignancies
A much lower impact of cisplatin on tumor growth was observed in the A2780cis observed in the A2780cis model with a growth inhibition of less than 30% (Figure 1)
Considerable progress in elucidating beneficial effects of heparin treatment of cancer has been documented during the lastintwo decades,beneficial which goes beyond the guideline-based application of Considerable progress elucidating effects of heparin treatment of cancer has been to circumvent or treat venous thrombotic events
Summary
Antithrombotic prophylaxis or treatment is a common component in the therapeutic regimes of patients with malignancies. Based on the current clinical guidelines for antithrombotic treatment of cancer patients, low molecular weight heparin (LMWH) is the drug of choice [2,3]. The retrospective analysis of those clinical data implies that anticoagulation by LMWH. Molecules 2017, 22, 728 could possess a survival benefit for certain cancer patients, which probably goes beyond solely an antithrombotic efficiency [4]. This postulate has been addressed by a high number of preclinical investigations during the last two decades to figure out the potential mode of action. LMWH was shown to affect the metastatic capacities of various carcinomas by interfering with different functional axes, such as cell adhesion [5], migration [6], chemokine and growth factor signaling [7] or the enzymatic activity of heparanase [8]
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