Oral (po) dosing with RSU 1069 or RB 6145 maintains their potency as hypoxic cell radiosensitizers and cytotoxins but reduces systemic toxicity compared with parenteral (ip) administration in mice

Journal Article · Mon Jul 01 04:00:00 EDT 1991 · International Journal of Radiation Oncology, Biology and Physics; (United States)

DOI:https://doi.org/10.1016/0360-3016(91)90787-5· OSTI ID:5459229

Cole, S; Stratford, I J; Bowler, J; Nolan, J; Wright, E G; Lorimore, S A; Adams, G E ^[1]

---

1. Medical Research Council, Radiobiology Unit, Didcot, Oxon (England)

RB 6145 is a pro-drug of the hypoxic cell radiosensitizer RSU 1069 with reduced systemic toxicity. The maximum tolerated dose (MTD) of RSU 1069 for C3H/He mice was 80 mg/kg (0.38 mmol/kg) ip but 320 mg/kg (1.5 mmol/kg) following po administration. The MTD values of RB 6145 were 350 mg/kg (0.94 mmol/kg) ip and 1 g/kg (2.67 mmol/kg) po. Toxicity of RSU 1069 toward bone marrow stem cells was also less after po administration than after ip administration; 0.1 mmol/kg ip RSU 1069 and 0.38 mmol/kg po RSU 1069 both reduced the surviving fraction of clonogenic CFU-A cells by 50%. Oral administration of RSU 1069 resulted in lower spermatogenic toxicity. No loss of intestinal crypts was detected after ip or po administration of RSU 1069. Some nephrotoxicity was observed in half of the mice given the highest po dose of 1.5 mmol/kg of RSU 1069; this was not observed following the highest ip dose of drug. For RSU 1069 and RB 6145, administered by either route, the maximum hypoxic cell radiosensitization in murine KHT sarcomas, occurred when the drugs were given 45-60 min before 10 Gy of X rays. The degree of radiosensitization produced by a particular dose of either compound was largely independent of the route of administration. Preliminary pharmacokinetic studies, using 3H-RSU 1069, suggested that anti-tumor efficacy correlated with peak blood level of label and concentration in the tumor at the time of irradiation, which were not reduced by po compared with ip administration. Normal tissue toxicity tended to correlate with total exposure over time, which was reduced approximately two-fold by po administration. Oral administration of RSU 1069 or RB 6145, as well as being convenient, may give therapeutic benefit since dose-limiting toxicity in mice was reduced compared with parenteral administration, whereas radiosensitizing activity was less affected.

• OSTI ID: 5459229
• Journal Information: International Journal of Radiation Oncology, Biology and Physics; (United States), Journal Name: International Journal of Radiation Oncology, Biology and Physics; (United States) Vol. 21:2; ISSN IOBPD; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

560152* -- Radiation Effects on Animals-- Animals
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
ANOXIA
COMPARATIVE EVALUATIONS
DRUGS
EVALUATION
EXPERIMENTAL NEOPLASMS
INJECTION
INTAKE
INTRAPERITONEAL INJECTION
MAMMALS
MICE
ORAL ADMINISTRATION
RADIOSENSITIZERS
RODENTS
TOXICITY
VERTEBRATES