Proceedings of the 37th Annual ASTRO Meet ing 243

1040 [MPLANTABLE BIODEGRADABLE POLYMERS FOR RADIOSENSITIZATION OF HUMAN GLIOMA IN VIVO

Jeffery Williams, M.D. ~'2, Larry E. Dillehay, Ph.D. ~, Eric Sipos, M.D. 2, Christian Fahlman, Ph.D. 1, Kevin Tabassi, M.D}, Jerry Williams, Sc.D. a, Moody Wharam, M.D}, Henry Brem, M.D. z

aRadiobiology Laboratory, Division of Radiation Oncology; 2Brain Tumor Research Laboratory, Department of Neurosurgery; The Johns Hopkins University School of Medicine, Baltimore, MD

Pumose: The potential of halogenated pyrimidines to radiosensitize human gliomas remains unrealized. Higher local delivery and lower systemic exposure may improve the therapeutic ratio. Synthetic, implantable, biodegradable polyanhydride polymers allow local, controlled, and sustained release of therapeutic agents. Their role in radiosensitization of tumors remains unexplored, however. Materials and Methods: I~ vitro: To measure release, increasing (10%, 30%, 50%) proportions of 5-iodo-2'-deoxyuridine (IUdR) in synthetic [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):.,ebacic acid (SA) (PCPP:SA ratio 20:80)] polymers (ca. 10 rag; lxlx3 ram) were incubated (1 ml PBS, 370 C) and the supematants serially assayed using HPLC. To measure modulation of release by a second, inert, co-loaded compound, 5-125-1-2'- deoxyuridine (125-IUdR) and increasing (10%. 30%, or 50%) proportions of D-glucose were combined in polymers, incubated in PBS, and the supernalants assayed. To test radiosensitization, cells (U251 human malignant glioma) were sequentially exposed to increasing (0, 0.1, 1.0, or 10 uM) concentrations of IUdR and increasing (0, 2.5, 5.0, or 10 Gy) doses of acute radiation. In vfvo: To measure release, polymers bearing 125-IUdR were surgically placed in U251 xenografts (0. l - 0.2 cc) growing in flanks of nude mice. The flanks bearing the tumors and polymers were reproducibly positioned over a collimated scintillation detector and counted. To measure radiosensitization, polymers bearing no (blank) or 50% unlabeled IUdR were placed in the tumor or contralateral flank. After three days tumors were acutely irradiated (500 cGy x 2 daily fractions). Results: In vitro: The initial rates of release of IUdR from polymers were high regardless of the percentage loading of IUdR, while the subsequent rates of release were proportionate to the percentage loading. The percentages of loaded IUdR recovered were 21.5, 23.3, and 18.7% in 6 h and 57.0, 73.5, and 92.4% after 11 days for 10, 30, and 50% loaded polymers, respectively. With 0, 10, 30, or 50% D-ghicose co-loading, cumulative release of radiolabeled IUdR was 21, 70, 92, or 97%, respectively. IUdR sensitized U251 cells to radiation in vitro. Compared to the highest radiation treatment alone, two additional logs of cell killing were observed following the combined l0 uM IUdR exposure and radiation. In vivo: Plot of activity over tumors with polymers bearing 125-IUdR showed apparent faster release when compared to the in vitro results. Percentages decline in activity (correlation coefficients) were 57 (0.83), 70 (0.76), 63 (0.85), 99 (0.97), 77 (0.91), and 74 (0.89) measured up to 267 h after implantation. After intratumoral blank or 50% IUdR-loaded vs. contralateral 50% IUdR-loaded polymer treatments, growth delays without radiation were 15.4 + 1.8, 20.1 4- 0.1, and 20.3 4- 3.6 (mean + SEM) (p = 0.488 one-way ANOVA) days. Tumors having blank polymers and radiation had average growth delays of 31.1 + 2.1 (p = 0.046 vs. polymer ,alone) days. After combined treatments with polymers bearing IUdR and radiation, average tumor volumes failed to increase four-fold. Therefore, times to grow back to the initial average volumes were compared. After contralateral or intratumoral placement of polymers having IUdR followed by radiation, growth delays of 14.0 + 3.6 or 24.2 + 0.2 (p = 0.001) days to return to the initial average volumes were recorded. Conclusions: Synthetic, implantable, biodegradable polymers allow sustained, predictable release of IUdR. Protraeled local administration of this agent to human glioma xenografts caused striking sensitization to acute irradiation. This technique holds promise for clinical radiosensitization of glioma and other human tumors using IUdR or other radiosensitizers. Supported in part by the Clinician Scientist Award and ACS Grant #IRG 11-34.

1041

LEUCOVORIN (LV) MODULATION OF IODODEOXYURIDINE (IdUrdl RADIOSENSITIZATION; A PHASE 1 STUDY

McGinn, Cornelius J.; Rodriguez, Rey; Kunugi, Keith A.; Tutsch, Kendra D.; Arzoomanian, Rhoda Z; Kinsella, Timothy J.

Department of Human Oncology, University of Wisconsin Medical School, Madison WI, 53792.

Purpose/Objectlve: Radiosensitization by the halogenated pyrimidine IdUrd has been demonstrated in laboratory studies and is directly related to the % thymidine replacement in DNA. hi vitro, the addition of LV increases both % thymidine replacement by IdUrd and radiosensitization by enhancing IdUrd mediated inhibition of thymidylate synthase, thus decreasing the endogenous (de novo ) source of thymidine monophosphate (Miller et al, Clin Cancer Res, 1995). This phase I s tudy was designed to assess the clinical feasibility of LV/IdUrd radiosensitization and evaluate the influence of LV on % thymidine replacement by IdUrd in vivo.

Materials & Methods: Patients with unresectable or locally recurrent GI adenocarcinomas received a continuous IV infusion of IdUrd for 14 days prior to initiation of radiotherapy. Two additional 14 day infusions of IdUrd were given during the course of radiotherapy (60 Gy in 6 weeks), both with the addition of LV. The initial dose of IdUrd was 250 m g / m 2 / d a y and was escalated in subsequent patients to 400 m g / m 2 / d a y and finally 600 mg/m2 /day . The LV dose remained fixed at 250 m g / m 2 / d a y . Patients were evaluated weekly for systemic and local toxicity. In addition, weekly blood samples were obtained for % thymidine replacement in peripheral blood granulocytes and pharn-tacokinetic analysis

Results: A total of 17 palnents have now been entered on this trial, the majority (11/17) with pancreatic cancer or liver metastasis. The max imum tolerated dose is 400 m g / m 2 / d a v , based on grade 3 systemic toxicity {predominantly neutropenia) in all 3 patients at the higher dose level. Correlative laborator i, studies b.ave been completed for patients on the first 2 dose levels. Percentage DNA incorporation b!,' IdUrd in peripheral blood granulocvtes increased with increasing IdUrd dose and by the addition of LV at each dose level as shown. Mean steady state plasma concentrations of IdUrd during the iiffusion were 0.56 pM _+ 0.07 and 0.66 _+ 0.23 in the 250 m g / m 2 / d a y and 400 m g / m 2 / d a y groups respectively.

Conclusion: The addition ot 1V 3ncreases % thvmidine replacement by combination has limited the MTD ot IdUrd to 400 m g / m 2 / d a v in patients with Support: NIH NO1-CM-073{}n, CA 50595

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