Doxorubicin uptake in ascitic lymphoma model: resistance or curability is governed by tumor cell density and prolonged drug retention

Abstract

Background/Aims: Chemotherapy resistance of malignancies is a universal phenomenon which unfavorably affects therapeutic results. Genetic adaptations as well as epigenetic factors can play an important role in the development of multidrug resistance. Cytotoxic drug content in plasma of cancer patients is known to variate up to one hundred-fold regardless of the same dose injected per m 2 body surface. The relationship between plasma concentrations, tissue uptake, and chemotherapy response is not completely understood. The main objective of this study was to investigate how the identical dose of Doxorubicin (Dox) can result in a different therapeutic response pattern depending on tumor size. Study Design: The study was performed on ascitic EL4 lymphoma in an exponential growth phase focusing on the rapidly changing tumor susceptibility to the Dox treatment. Well distinguishable tumor response patterns (curability, remission-relapse, resistance) were selected to unveil Dox intratumoral uptake and drug tissue persistence. Intratumoral Dox content within peritoneal cavity (PerC) in conjunction with systemic toxicity and plasma pharmacokinetics, were monitored at several time points following Dox injection in tumor bearing mice (TBM) with differing patterns of response. Results: Following intraperitoneal (i.p.) transplantation of 5x10 4 EL4 lymphoma cells rapid exponential proliferation with ascites volume and animal mass increase resulted in median survival of 14.5 days. The increase in tumor cell mass in PerC between day 3 and day 9 was 112.5-fold (0.2±0.03 mg vs 22.5±0.31 mg respectively). However, tumors at this time interval (day 3 to day 9 post-transplantation) were relatively small and constituted less than 0.05% of animal weight. An identical dose of Dox (15 mg/kg) injected intravenously (i.v.) on Day 3 lead to a cure whereas a TBM injected on day 9 exhibited resistance with a median survival time no different from the untreated TBM control. Injection of Dox resulted in noticeable differences of cellular uptake in PerC between all three groups of TBM ("cure", relapse", "resistance"). Larger tumors were consistently taking up less Dox 60 min after the 15 mg/kg i.v. bolus injection. Higher initial uptake resulted also in longer retention of drug in PerC cells. The area under the concentration curve in PerC cells AUC0-10d was 8.2+0.57 µg/g x h, 4.6+0.27 µg/g x h and 1.6+0.02 µg/g x h in "cure", "relapse" and "resistance" TBM respectively (p<0.05 "relapse" vs "cure" and p<0.001 "resistance" vs "cure"). No differences in plasma Dox pharmacokinetics or systemic hematological effects were observed in TBM following a single i.v. Dox push. Hematologic nadir was tested on day 2 and subsequent hematologic recovery was evaluated on day 10 following Dox administration. Hematologic recovery on day 10 coincided with complete drug efflux from PerC and rising tumor cell numbers in PerC of "relapse" TBM. Myelosuppression and hematological recovery patterns were identical in all surviving animal groups regardless of the tumor si...

Maleimide-Functionalized Liposomes: Prolonged Retention and Enhanced Efficacy of Doxorubicin in Breast Cancer with Low Systemic Toxicity

“…Liposome size is known to affect the stability, uptake, and metabolism of liposome-based formulations [ 26 ]. We found that Lip and M-Lip were spherical nanoparticles with a similar size of ~100 nm ( Figure 1 A,C).…”

Long noncoding RNA SATB1-AS1 contributes to the chemotherapy resistance through the microRNA-580/ 2’-5’-oligoadenylate synthetase 2 axis in acute myeloid leukemia

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Low dose chemotherapy induces a dormant state in brain metastatic breast cancer spheroids

“…9,10 Owing to the heterogeneity of solid tumors, lower doses of chemotherapeutic drugs reach the tumor site than the dose administered. 11 Zaleskis et al, reported that similar doses of chemotherapeutic drug (doxorubicin) administered in tumor bearing mice resulted in three different responses (cure, resistance, and relapse), 12 explaining the important role of heterogeneous cell populations. Chemotherapy drugs are also known to be present in the associated tissue for longer periods of time.…”