Mustard blood partition: differences between rodents and cancer patients, and the consequences for anticancer drug development


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Martin Highley1, Hans Prenen2, Zidang Zang2, Ernst De Bruijn2

1Plymouth Oncology Centre, Derriford Hospital, Plymouth, UK, 2Laboratory of Experimental Oncology, University of Leuven, Belgium

Abstract

Background

Mustard related anticancer agents have been central to clinical and experimental oncology for 50 years. We have previously demonstrated that mustard analogues exhibit a more profound dose schedule dependent cytotoxicity in rodents compared to humans; this cannot be explained solely by differences in metabolism. Partition studies exploiting sediment technologies1,2, indicate different blood partitioning of mustard moieties depending on the dose schedule. The study aimed to determine the impact of mustard blood partition on the efficacy of mustard analogues in humans and small rodents.

Method

Blood from human volunteers, and blank blood from cancer patients, rats and mice, was exposed for 1 hr to therapeutic concentrations of phosphoramide mustard (PM). Red Blood Cells (RBCs), plasma and plasma water were obtained by MESED procedures. PM was determined by LC.

Results

RBCs and plasma water from all species were loaded in a dose dependent manner, with the steepest curves in the RBCs of rat and mouse blood. The maximum percentages of RBCs and plasma water partition versus total blood were significantly higher in the rat (76% and 79%) and mouse (81% and 85%), when compared to human blood (53% and 49%). In each species, the PM present on/in the RBCs could be washed off completely with blank plasma from that species.

Conclusion

The blood partition of PM differs in humans and small rodents. The partition profiles in small rodents may account for the striking higher activity of mustard analogues in small laboratory tumour bearing animals compared to cancer patients, a phenomenon not yet fully explained. Furthermore, the ability of RBC mustard concentration to predict antitumour activity2 is now better understood. Blood partition studies should be employed routinely in new anticancer drug development.

References

[1] Driessen et al. Clin Biochem; 27: 195-6 (1994).

[2] Wildiers et al. Int J Cancer; 99: 514-9 (2002).