We argue that drugs that specifically target mitosis will be more effective if mitosis is common and less so if mitosis is rare. Hence, the occurrence of myelosuppression, following therapy with microtubule-targeting agents and with mitosis-specific agents, reflects the high mitotic activity in the bone marrow, and shows that both classes of agents effectively target mitosis when it is present. The lack of response to mitosis-specific agents in patient tumors is then consistent with the relative rarity of mitosis in tumors. Accordingly, we and others (1, 2) have argued that the activity of microtubule-targeting agents against patient tumors must be mostly due to effects on targets not restricted to mitosis. These may include signaling pathways that are often microtubule-dependent and which occur throughout the cell cycle.

Tunquist and colleagues argue that apoptotic signaling pathways can play an important role in determining response to chemotherapy, a point with which we would heartily agree. But if degradation of Mcl-1, or any other protein, occurs primarily during mitosis, it may nevertheless be difficult for an agent targeting mitosis to result in much Mcl-1 degradation, unless of course an off target effect leads to the disappearance of Mcl-1. Alternately, we would suggest that signaling pathways that support cancer cell survival may be targetable at points in the cell cycle other than mitosis. The latter may be accomplished either directly by targeting pathway elements or indirectly by targeting the microtubules as these may play critical roles in some signal transduction pathways.

Wissing and colleagues make points we agree with and points with which we disagree. We agree that mitotic enzymes have been reported to be overexpressed in some cancers and that they may play a role beyond mitosis. In a cancer where such a “nonmitotic” role exists and is crucial, an inhibitor might be an excellent drug—albeit not as a mitotic inhibitor but as an inhibitor of another, yet to be identified function. We were not arguing against this view. We also agree that mitotic slippage often leads to cell death but would disagree that this would commonly occur in a tumor that is not dividing all that rapidly and hence would not be an outcome that would add much to the antitumor activity of a mitotic inhibitor.

As for the suggestions by Wissing and colleagues that improving oral bioavailability, other pharmacokinetic properties, or tumor-specific activation might enhance activity, we do not think this will do much to increase its antimitotic activity as these are limited by the growth rate of tumors. The suggestion that granulocyte-colony stimulating factor may help, in fact acknowledges, what we said—these are great drugs for rapidly dividing cells such as those found in the bone marrow—but unfortunately not for slow growing tumors. While one wishes it were otherwise, we remain convinced that there is a low likelihood that any of these maneuvers will be able to generate much from drugs with activity to date in the low single digits.

See the original Letter to the Editor, p. 1302

See the original Letter to the Editor, p. 1303

No potential conflicts of interest were disclosed.

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