Cynthia Sung

Intraventricular immunotoxin therapy for leptomeningeal neoplasia.

OBJECTIVEnThe goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity.nnnMETHODSnWe performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454A12-rRA is a conjugate of a monoclonal antibody against the human transferrin receptor and recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. Patients were treated with single doses of 454A12-rRA ranging from 1.2 to 1200 micrograms.nnnRESULTSnThe early phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (CSF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than the clearance of coinjected technetium-99m-diethylenetriamine penta-acetic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degradation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling the concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 micrograms of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 micrograms caused a CSF inflammatory response that was associated with transient headache, vomiting, and altered mental status. This acute syndrome was responsive to steroids and CSF drainage. No systemic toxicity was detected. In four of the eight patients, a greater than 50% reduction of tumor cell counts in the lumbar CSF occurred within 5 to 7 days after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance imaging evidence of tumor progression was demonstrated in seven of the eight patients after treatment.nnnCONCLUSIONnTumoricidal concentrations of the immunotoxin 454A12-rRA can be attained safely in the CSF of patients with leptomeningeal tumor spread.

Intrathecal administration of topotecan in nonhuman primates

The cerebrospinal fluid (CSF) pharmacokinetics of topotecan were studied in a nonhuman primate model following intraventricular administration of 0.1 mg. Lactone and total drug concentrations were measured using a reverse-phase HPLC method with fluorescence detection. The mean peak concentrations of lactone and total drug in ventricular CSF were 83±18 μM and 88±25 μM, respectively. CSF drug elimination of the lactone was bi-exponential with a terminal half-life of 1.3 h. The mean clearance from ventricular CSF was 0.075 ml/min for the lactone and 0.043 ml/min for total drug. The ventricular CSF drug exposure (AUC) to lactone was 450-fold greater following intraventricular administration of 0.1 mg topotecan than after systemic intravenous administration of a 40-fold higher dose (10 mg/m2). Peak lumbar concentrations (n=1), which occurred 2 h after intraventricular drug administration, were 0.98 μM and 2.95 μM for the lactone and total drug, respectively. A transient CSF pleocytosis was observed in one animal following intraventricular topotecan administration and in one animal following intralumbar topotecan administration. No other acute or chronic neurologic or systemic toxicities were observed following a single intraventricular dose or weekly (×4) intralumbar topotecan. Compared with systemic topotecan, intrathecal administration provided a significant pharmacokinetic advantage in terms of CSF drug exposure and did not produce any significant neurotoxicity in a nonhuman primate model. Intrathecal topotecan should be evaluated clinically as a potential alternative therapy for refractory meningeal tumors.

Effect of angiotensin II on immunotoxin uptake in tumor and normal tissue

Abstractu2003Purpose: To investigate the effect of the sarcosine analog of human angiotensin II ({sar}ATII) on the uptake and spatial distribution of immunotoxins (MW 210000 Da) in RD rhabdomyosarcoma xenografts in mice. This analog has a pressor activity similar to native angiotensin II (ATII) but a longer duration of action. Method: A period of elevated blood pressure of approximately 80 min, measured by noninvasive photoplethysmography, was achieved by a 40-min continuous i.p. infusion of {sar}ATII at 0.07 μg/min. Tumor-bearing animals were injected i.v. with 125I-labeled specific and 131I-labeled nonspecific immunotoxins and made hypertensive by i.p. infusion of {sar}ATII. Radioactivity was measured in plasma, tumor, liver, kidney and muscle at 2, 6 and 24 h. Plasma radioactivity was subtracted from tissue values to calculate tissue uptake. To assess the spatial distribution of immunotoxin in the solid tumor, 125I-labeled specific immunotoxin was injected i.v. into tumor-bearing animals, and quantitative autoradiography was performed on tumor sections. Results: The uptake of specific or nonspecific immunotoxins in tumor and normal tissues was not significantly different in {sar}ATII-hypertensive animals compared with saline-treated controls. In control animals, the spatial distribution of 125I-labeled specific immunotoxins was very heterogeneous and contained punctate accumulations throughout the tumor. Treatment with {sar}ATII did not affect this distribution qualitatively or quantitatively. To examine a possible reason for the lack of {sar}ATII effect, we measured the interstitial pressure of the RD tumor using a fluid-filled micropipette connected to a servo-null pressure transducer. The interstitial pressure in this solid tumor was unexpectedly low, only 0.6±0.9 mm Hg. Conclusions: The sustained period of{sar}ATII-induced hypertension had no effect on RD tumor or normal tissue uptake or tumor spatial distribution of immunotoxin. In saline-treated controls, the heterogeneity of immunotoxin distribution does not arise from an elevated interstitial pressure. Further studies are needed to determine whether a correlation exists between responsiveness to ATII-induced hypertensive chemotherapy using macromolecular drugs and tumor type and/or physiological properties.