Polymeric retinoid prodrug PG-4HPR enhances the radiation response of lung cancer

Abstract

Abstract.To determine whether a polymer-drug conjugate might improve tumor cell kill compared to the corresponding unconjugated agent when used in combination with radiation, we examined the antitumor activity of a water-soluble conjugate of N-(4-hydroxyphenyl) retinamide (4HPR) and poly(L-glutamic acid), PG-4HPR, in lung cancer cells and xenografts. The antiproliferative activity of 4HPR and PG-4HPR in human lung cancer A549 cells was evaluated and the response of the cells to radiation measured by clonogenic assay. Response to irradiation was evaluated by measuring tumor growth delay in nude mice bearing intramuscularly inoculated A549 tumors. Histologic responses were assessed by examination of apoptosis (TUNEL assay) and cell proliferation (Ki67 staining). In vitro, 4HPR and PG-4HPR inhibited the proliferation of A549 cells, with IC 50 values of 25.8 μM and >50 μM, respectively, after 24 h of continuous exposure and 6.25 μM and 9.75 μM, respectively, after 120 h. Both agents increased radiosensitivity at an equivalent 4HPR concentration of 10 μM after 5 days of exposure, with enhancement factors of 1.40 and 1.43. In tumor xenografts, intravenous injection of 4HPR or PG-4HPR (30 mg eq. 4HPR/kg) enhanced radiosensitivity by 1.3 and 1.6, respectively, without apparent systemic toxicity. PG-4HPR augmented radiation-induced apoptosis and decreased cellular proliferation in vivo. The radiation response of A549 tumors was greater with PG-4HPR than with 4HPR, which may be attributed to increased delivery of 4HPR to the tumors and enhanced apoptotic response. These results suggest that a polymeric delivery system may be useful for modulating radiosensitivity. IntroductionIt has been shown that the addition of concurrent chemotherapy to radiotherapy (chemoradiotherapy) results in improved clinical outcome in terms of both locoregional control and overall survival in some groups of patients (1-3). However, chemoradiotherapy is often associated with severe, dose-limiting toxicities that limit its application. For example, Liao et al (4) found that the combination of twice-daily radiotherapy (XRT) and concurrent cisplatin/etoposide resulted in a favorable long-term outcome (26%, 5-year survival rate), but it also increased the incidence of more severe radiationinduced pneumonitis and esophagitis. Furthermore, most chemoradiotherapy regimens are platinum-based and there is evidence that the maximum tolerable toxicity has been reached with the dose intensities currently used in bolus cisplatin regimens. Therefore, new means are being explored to selectively target tumors with chemotherapeutic agents to reduce normal tissue toxicity and maximize antitumor efficacy.One approach to improve the efficacy of radiotherapy without increasing its side effects is to use molecularly targeted therapeutic agents such as epidermal growth factor receptor and vascular endothelial growth factor receptor inhibitors (1,5). The fact that the specificity of such agents will be high by design has given rise to the expectation that targeted drug...

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“…4HPR has been shown to inhibit carcinogenesis in a variety of cancer cells, including breast cancer (2), bladder cancer (3), lung cancer (4), prostate cancer (5) and leukemia (6–7). Clinical trials have shown that 4HPR induces a significant reduction of secondary breast cancers in premenopausal women (8).…”

Peptide-Targeted Polyglutamic Acid Doxorubicin Conjugates for the Treatment of αvβ6-Positive Cancers

“…The MALDI mass spectrum was obtained in reflector mode using R-cyano-4-hydroxycinnamic acid as matrix. Maleimido-PEG-polyGlu 15 Incorporation of H 2 NNHBoc to Pendant Carboxyl Group of Maleimido-PEG-polyGlu 15 . The hydrazide groups were conjugated to the pendant carboxyl groups of compound 1 via acid anhydride reaction.…”

“…As such, greater drug loads can be achieved based on a per molecule basis. This carrier has been used for doxorubicin − , paclitaxel − , camptothecin , , and retinoids , . In addition, MRI contrast reagents have been coupled to PG for tumor imaging − .…”