Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia

Abstract

Combined radioimmunotherapy (RAIT) and hypoxic cytotoxin therapy (SR4233 or NLCQ-1) have been evaluated with both modalities administered on the same day with only moderate improvement compared with the effects of RAIT alone. In a series of studies using oxygen electrodes, immunohistochemistry and radiotracers, we have demonstrated that RAIT induces a prolonged state of hypoxia in most tumors, without affecting the pO 2 levels in normal tissues. Using serial microelectrode measurements through subcutaneous (s.c.) GW-39 human colonic xenografts, we established that the median pO 2 was unrelated to the initial size of the tumor, over a range of sizes from 1.0 to 4.0 cm. Fourteen days after mice were given a 240-Ci dose of 131 I-MN-14 anti-carcinoembryonic antigen immunoglobulin G, their median pO 2 declined from 26.1 ؎ 9.6 mmHg to 9.8 ؎ 3.9 mmHg (p < 0.001). Using the radiotracer 3 H-MISO that accumulates in hypoxic regions, uptake in GW-39, LoVo and LS174T s.c. human colonic tumors increased 3.0-to 4.2-fold from day 14 through day 28 post-RAIT, but uptake of 3 H-MISO in CALU-3 tumors remained unchanged after RAIT. Normal tissue (liver, kidney, lung) uptake of 3 H-MISO did not exhibit significant changes. The increase in tumor hypoxia was also demonstrated visually using anti-PIMO staining of tumor sections. We postulated that sequential delivery of the 2 therapeutic agents, with the hypoxic cytotoxin given 2 weeks after RAIT when tumor pO 2 levels were at their nadir, would improve the therapeutic response above either modality alone or above the 2 agents delivered on the same day. Tumor growth was compared in mice given either RAIT or cytotoxin alone, the combined treatment on the same day or with the cytotoxin delivered 14 days after RAIT. Tumor size on day 35 for RAIT-treated and SR4233-treated GW-39 were 3.56 ؎ 0.40 and 7.98 ؎ 2.50 cm 3 . When RAIT ؉ SR4233 were delivered on the same day, tumor size dropped to 2.78 ؎ 0.80 cm 3 . If RAIT was given on day 0 and SR4233 on day 14, size further declined further to 1.74 ؎ 0.32 cm 3 (p < 0.05 compared with same day delivery). For LS174T, tumor size on day 28 for RAIT-treated and SR4233-treated tumors were 1.14 ؎ 0.36 cm 3 and 3.65 ؎ 0.78 cm 3 , respectively. When RAIT ؉ SR4233 were delivered on the same day, size was 0.51 ؎ 0.174 cm 3 . If RAIT was dosed on day 0 and SR4233 was given on day 14, tumor size was 0.13 ؎ 0.07 cm 3 (p < 0.05). Similar results were obtained for LoVo, but not for CALU-3 tumors. Another hypoxic cytotoxin, NLCQ-1, was also more efficacious 2 weeks after RAIT, compared with same-day dosing. Thus, information on tumor hypoxia after radioantibody therapy could be important for ascertaining a window of opportunity when the surviving tumor regions are most responsive to hypoxic cytotoxins.

Low-Dose Metronomic Daily Cyclophosphamide and Weekly Tirapazamine: A Well-Tolerated Combination Regimen with Enhanced Efficacy That Exploits Tumor Hypoxia

“…Accordingly, Blumenthal et al showed that hypoxic cell cytotoxin therapy can be optimized in vivo as a function of tumor oxygenation (56). In addition, stratification for the degree of hypoxia before start of treatment significantly improved the results of a clinical trial involving chemoradiation with or without tirapazamine (57).…”

Advantage of Combining NLCQ-1 (NSC 709257) with Radiation in Treatment of Human Head and Neck Xenografts

“…In previous studies of human colon tumor xenografts, NLCQ-1 demonstrated significant antitumor activity in combination with radioimmunotherapy only when it was administered 14 days after radioimmunotherapy, when the radioimmunotherapy-induced tumor hypoxia (measured with oxygen microelectrodes, anti-PIMO staining or the radiotracer 3 H-MISO) was maximum (33). NLCQ-1 also caused significant growth delay on its own only in EMT6 mouse mammary tumors positive to the hypoxia tracer 18 F-FAZA (unpublished results).…”

Antitumor Effects of a Human Dimeric Antibody Fragment 131I-AFRA-DFM5.3 in a Mouse Model for Ovarian Cancer

“…In fact, dose fractionation has been proposed to improve the therapeutic effects of radioimmunotherapy (26,27). Furthermore, because radioimmunotherapy is able to modify vascular permeability and tumor hypoxia, favoring the following pharmacologic therapy treatment (28)(29)(30), combined treatments could be envisioned.…”