Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer.

Advanced ovarian cancer currently has few therapeutic options. Poly(ADP-ribose) polymerase (PARP) inhibitors bind to nuclear PARP and trap the protein-inhibitor complex to DNA. This work investigates a theranostic PARP inhibitor for targeted radiopharmaceutical therapy of ovarian cancer in vitro and PET imaging of healthy mice in vivo. METHODS: [77Br]RD1 was synthesized and assessed for pharmacokinetics and cytotoxicity in human and murine ovarian cancer cell lines. [76Br]RD1 biodistribution and organ uptake in healthy mice were quantified through longitudinal PET/CT imaging and ex vivo radioactivity measurements. Organ-level dosimetry following [76/77Br]RD1 administration was calculated using RAPID, an in-house platform for absorbed dose in mice, and OLINDA for equivalent and effective dose in human. RESULTS: The maximum specific binding (Bmax), equilibrium dissociation constant (Kd), and nonspecific binding slope (NS) were calculated for each cell line. These values were used to calculate the cell specific activity uptake for cell viability studies. The half maximal effective concentration (EC50) was measured as 0.17 (95 % CI: 0.13-0.24) nM and 0.46 (0.13-0.24) nM for PARP(+) and PARP(-) expressing cell lines, respectively. The EC50 was 0.27 (0.21-0.36) nM and 0.30 (0.22-0.41) nM for BRCA1(-) and BRCA1(+) expressing cell lines, respectively. When measuring the EC50 as a function of cellular activity uptake and nuclear dose, the EC50 ranges from 0.020 to 0.039 Bq/cell and 3.3-9.2 Gy, respectively. Excretion through the hepatobiliary and renal pathways were observed in mice, with liver uptake of 2.3 ± 0.4 %ID/g after 48 h, contributing to estimated absorbed dose values in mice of 19.3 ± 0.3 mGy/MBq and 290 ± 10 mGy/MBq for [77Br]RD1 and [76Br]RD1, respectively. CONCLUSION: [77Br]RD1 cytotoxicity was dependent on PARP expression and independent of BRCA1 status. The in vitro results suggest that [77Br]RD1 cytotoxicity is driven by the targeted Meitner-Auger electron (MAe) radiotherapeutic effect of the agent. Further studies investigating the theranostic potential, organ dose, and tumor uptake of [76/77Br]RD1 are warranted.

Sex inequality in kidney transplantation rates.

BACKGROUND: Men in the United States undergoing renal replacement therapy are more likely than women to receive a kidney transplant. However, the ability to pay may, in part, be responsible for this finding. OBJECTIVE: To compare adult male and female transplantation rates in a setting in which equal access to medical treatment is assumed. METHODS: Using data from the Canadian Organ Replacement Register, the rate of first transplantations was computed for the 20, 131 men and the 13,458 women aged 20 years or older who initiated renal replacement therapy between January 1, 1981, and December 31, 1996. Poisson regression analysis was used to estimate the male-female transplantation rate ratio, adjusting for age, race, province, calendar period, underlying disease leading to renal failure, and dialytic modality. Actuarial survival methods were used to compare transplantation probability for covariable-matched cohorts of men and women. RESULTS: Men experienced 20% greater covariable-adjusted kidney transplantation rates relative to women (rate ratio, 1.20; 95% confidence interval, 1.13-1.27). The sex disparity was stronger for cadaveric transplants (rate ratio, 1.23) compared with those from living donors (rate ratio, 1.10). The 5-year probability of receiving a transplant was 47% for men and 39% for women within covariable-matched cohorts (P<.001). The sex disparity in transplantation rates increased with increasing age. The sex effect was weaker among whites and Oriental persons (Chinese, Japanese, Vietnamese, Cambodian, Laotian, Filipino, Malaysian, Indonesian, and Korean) and stronger among blacks, Asian Indians (Indian, Pakistani, and Sri Lankan), and North American Indians (aboriginal). CONCLUSION: Since survival probability and quality of life are superior for patients who undergo transplantation relative to those who undergo dialysis, an increased effort should be made to distribute kidneys available for transplantation more equitably by sex among patients undergoing renal replacement therapy.