Table 1.

NAb response and systemic toxicity of i.v. reovirus in combination with different cyclophosphamide regimens

Serum from mice treated with:Range of neutralizing titerToxicities observed
PBSNone*NDT
Reo>1:1,280NDT
Reo/low CPA1:160-1:320NDT
Reo/high CPANone*Lethargic; thin; difficulty in breathing; fluid build up s.c. and in organs; found dead; swollen tails; tail detached; severe myocarditis/calcification
Reo/metro CPA1:40-1:80No gain of body weight
  • NOTE: C57Bl/6 mice bearing 6-d established s.c. B16 tumors were treated with PBS; three i.v. injections of 5 × 108 pfu of reovirus (Reo; as described in Fig. 1B); with low-dose cyclophosphamide + three i.v. injections of 5 × 108 pfu of reovirus (Reo/low CPA; as described in Fig. 2A); with high-dose cyclophosphamide + three i.v. injections of 5 × 108 pfu of reovirus (Reo/high CPA; Fig. 2A); or with metronomic dosing of reovirus + cyclophosphamide (Reo/metro CPA; Fig. 4A). NAb was measured from the serum of treated mice as described in Materials and Methods upon euthanasia of the mice due to either systemic toxicity or tumor size. The ranges of typical levels of NAb are shown to indicate any difference between mice. The major toxicities observed in different treated groups are described; not every mouse treated necessarily developed each of the symptoms.

    Abbreviations: NDT, no detectable toxicity; CPA, cyclophosphamide; Reo, reovirus.

  • * Preincubation of serum with reovirus was not able to reduce the toxicity to L929 cells to any greater extent than DMEM.

  • No detectable toxicity was observed upon three doses of 5 × 108 pfu of reovirus administered 6 d apart; however, when three doses of 1.1 × 1010 pfu were administered 6 d apart, one of nine mice developed severe toxicity including loss of weight and a swollen and red tail that eventually became detached.

  • No detectable toxicity was observed upon three doses of 5 × 108 pfu of reovirus administered 6 d apart; however, when three doses of 1.1 × 1010 pfu were administered 6 d apart, nine of nine mice developed lethargy and chills; several mice had edema with organs full of fluid and one of nine was found dead.