The Effect of Various Therapeutic Solutions including Colloidal Chromic 32p via an Intratumoral Injection on the Tumor Physiological Parameters of AsPC-1 Human Pancreatic Tumor Xenografts in Nude

To overcome the physiological barrier in solid tumors (i.e., tumor hypertension), a large volume of material is required via an intratumoral injection. Alternatively, a method of reduction in tumor hypertension is also feasible. In this study, we focused on the physiological response after an intratumoral infusion of various therapeutic agents. Tumor interstitial fluid pressure (TIFP) was intermittently monitored for up to 7 days after treatment using AsPC-1 human pancreatic tumors in nude mice. Macroaggregated albumin (MAA), colloidal chromic 32p (32p . cp ) , albumin, dexamethasone, 5-fluoro-2'deoxyuridine, dextrose, saline, and trypan blue increased T I F P within --5 min , a n d T I F P returned to the original level within 1 h, except in the case of MAA and 3 2 p c P . We also found that the maximal uptake for AsPC-1 tumors in both the exponential and plateau growth phases occurred at --100 min postincubation; the m a x i m u m value in the exponential growth phase was 2 times less than that of plateau growth phase (P < 0.01). Therefore, this study supports intralesional 32p-cP brachytherapy for nonresectional pancreatic cancer patients. This may offer a promising treatment modality for delivering high doses of tumor-selective radiation, mainly due to two physiological mechanisms: (a) the high adherence of 32p-cP to the infused regions; and (b) reduction in either tumor blood flow or TIFP by this therapeutic colloid. Presented at the "Seventh Conference on Radioimmunodetection and Radioimmunotherapy of Cancer," October 15-17, 1998, Princeton, NJ. Supported by grants from the New Jersey State Commission on Cancer Research (to I. L.) and the AlfaCell Corp., Bloomfield, New Jersey (to I. L.). This work was performed at the Radiation Research Laboratory, Division of Radiation Research, UMDNJ-Robert Wood Johnson Medical School, Camden, New Jersey. This laboratory was closed in December 1998 due to lack of research funds. 2 To whom requests for reprints should be addressed. Present address: Department of Radiation Oncology, University of Pennsylvania School of Medicine, 195 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6072. Phone: (215) 898-0071 ; Fax: (215) 898-0090, E-mail: ilee2 @ mail.med.upenn.edu, Introduction Rapid advances in the molecular biology of cancer have led to the development of various genetically engineered molecules, including monoclonal antibodies as well as other useful macromolecules. Due to the elevated TIFP, 3 radiolabeled monoclonal antibodies and gene therapy in cancer treatment have not been as effective as anticipated. To overcome this physiological barrier, administration of a large volume of material via an i.t. injection is required. When a therapeutic agent is mixed with a large quantity of fluid directly infused into the center of a tumor, it increases the pressure at the core of the tumor relative to its surroundings. Consequently, the drug spreads along an artificially induced pressure gradient by convection from the core through the surrounding region and into the periphery (1). To elucidate physiological response alter an i.t. infusion (volume, 100 ~xl) of various therapeutic agents, TIFPs were intermittently monitored up to 7 days posttreatment. Several relevant materials such as saline (0.9% or 30% NaC1), 32p-cP, MAA (105 or 10 7 particles), human albumin (--2.5 mg/ml), 30% dextrose, dexamethasone (1 mg/ml), 5-fluoro-2'-deoxyuridine (500 ms/ks) , RNase-like ONC, and trypan blue (0.4%) were used on AsPC-1 human pancreatic carcinoma xenografts in nude mice. This study supports the hypothesis that if 32p-cP was introduced intratumorally, it would maintain highly efficient tumor targeting by 3~P-CP-induced physiological mechanisms. Materials and Methods Animals and Tumors. Female 8-10-week-old nude mice (Cox Animal Facility, Massachusetts General Hospital, Boston, MA) were used, and they were kept under pathogenfree conditions in the vivarium maintained at 25~ + 3~ AsPC-1 tumor cells were cultured, and they were grown in vitro. Single cell suspensions were prepared using 0.25% trypsin solution. About 1 • 106 viable cells suspended in 50 Ixl of HBSS were injected s.c. into the right thighs of mice. Experiments were carried out when the tumor volume was 5 0 0 m m 3 (2). In Vitro 32p-cP Cellular Uptake Measurements. AsPC-1 cells were plated in 24-multiwell plates and then incubated to grow in either the exponential or plateau growth phase. After exposure to 10 p~Ci of 32p-cP (Mallinckrodt Medical, Inc., 3 The abbreviations used are: TIFP, tumor interstitial fluid pressure; i.t., intratumoral; MAA, macroaggregated albumin; 32p-cP, colloidal chromic 32p; TBF, tumor blood flow; ONC, onconase; IFP, interstitial fluid pressure; WIN, wick-in-needle. Research. on October 16, 2017. © 1999 American Association for Cancer clincancerres.aacrjournals.org Downloaded from 3140s Tumor Targeting by an Intratumoral Injection