Differential effect of IP- and IV-injected nitrogen mustard on subsequently-irradiated intestinal crypts: implications for 'dose-effect factors' predicted by experimental, combined modality therapy.

Abstract

In experimental chemotherapy-radiotherapy, cytotoxic drugs are almost invariably injected by the intraperitoneal (IP) route. This contrasts with normal clinical practice, which is to employ the intravenous (IV) route. We have used a clonogenic assay of gastrointestinal (GI) injury in mice to show that a given administered dose of nitrogen mustard (HN2), injected IP, results in a much greater reduction in the subsequent radiation dose required to achieve an isoeffect, than if the drug is injected IV. At an administered dose of 3.5 mg kg-1 of HN2 (the animal LD10/30 for IP injection), the radiation dose-reduction factor for 10% survival of intestinal crypts, was 1.94 for IP HN2 and only 1.28 for IV HN2. Even the grossly-equitoxic (mouse LD10/30) dose of IV HN2 resulted in a smaller predicted radiation dose reduction for GI injury, by a factor of 1.45. The validity of using the IP route in combined chemotherapy-radiotherapy studies designed to generate quantitative estimates of toxicity is discussed.