Tannous et al. Respond:

We thank Drs Lemaire and Halperin for their comments on our article in Molecular Therapy.^1,2 They raise important concerns about the effects of rapid cell lysis on the physiology of nontumor tissues; these effects have been recognized as tumor lysis syndrome and are of particular concern in cancers with high cell turnover rate, such as lymphomas and leukemias. However, we think that the time course of cell death (hours to days) will spread these effects over a period sufficiently long that normal homeostatic mechanisms will buffer the ionic effects of tumor cell death.

  1. The mutant Na⁺ channel has a relatively rapid killing effect on tumor cells in culture. Yet even in culture, cells die over a period of 6–12 hours, and they do not die synchronously. Moreover, the scenario is different in vivo: only a fraction of tumor cells (~5%) are likely to be infected initially, and death of adjacent cells is a slower event that depends on the extent of gap-junctional contact. Thus, cell death and lysis of the tumor happen over days, as observed in our in vivo subcutaneous tumor models. This should dampen the effect on intracranial pressure. In the very-worst-case scenario, drugs such as steroids and bevacizumab could be administered orally to reduce the edema. These are commonly used clinically to reduce the edema caused by other relatively rapid therapies that destroy tumors, such as radiation therapy and stereotactic radiosurgery.

  2. If all the intracellular K⁺ of all the tumor cells were released as a bolus, it might well cause arterial hyperkalemia. However, release over a period of hours would allow mixing with the general circulation. Moreover, the effect would not be terribly large; as an extreme example, if all the intracellular K⁺ from a 4-cm tumor was suddenly added to the blood, it might cause an elevation of serum K⁺ by about 1 mEq/L. Hyperkalemia from cell lysis over hours would be much less.

  3. We agree that cell lysis may cause local precipitation of calcium phosphate and local hypocalcemia. To the extent that these are toxic to nearby cells, it could add to the bystander tumor-killing effect. However, if the effect were large, we agree that there could be kidney damage with deposition of calcium phosphate crystals in the renal parenchyma, which is seen following chemotherapy of cancers with a high cell turnover rate. Treatment would be similar to that for tumor lysis syndrome.

  4. Similarly, if high ATPase activity by the Na⁺−K⁺-ATPase of infected cells led to local acidosis and hypoglycemia, it would enhance the bystander effect, generally a good thing in treating aggressive tumors.

  5. We agree that Na⁺ influx will be followed by both Cl^– influx and K⁺ efflux as infected cells are depolarized.

As with any new therapy, there may be unanticipated problems from rapid and effective killing of tumor cells. We think that most of these will be similar to those of other rapid therapies, such as radiation therapy and stereotactic radiosurgery, for which treatments are being developed. Overall, we hope that the benefits of effective tumor killing with mutant ion channels will outweigh any collateral damage.