At the same time, part of the proven therapeutic value for the benzyl derivative probably stems from the fact that it does not require monooxygenase activity for activation to the sulfenic acid of vitaletheine. Non-enzymic activation probably requires two physical processes, an equilibrium favoring at least temporary restoration of a calcium or similar cationic bridge followed by removal of the cation, this time without an associated dehydration. The first condition might be most prevalent in rapidly dividing cells, since higher intracellular calcium concentrations are associated with proliferative responses. It follows that nonenzymic activation of the benzyl derivative in resting cells might be less prevalent than in rapidly dividing cells since calcium is maintained at a low level in the former. This particular hypothesis, activation of the prodrug by changes in calcium concentrations, helps to explain why the benzyl derivative is effective in treating myeloma at concentrations 1,000 to 3,000 times higher than those concentrations of vitalethine found to be most effective in treating melanoma. Whether or not this proposed selective mechanism in any way assists in the recognition and elimination of tumor cells by the immune system is not yet known, but it is clear that the benzyl derivative has therapeutic advantages over those demonstrated for vitalethine.
It is not clear whether the same potencies holds for all salt complexes of the benzyl derivative, the calcium one having been tested most extensively, nor is it clear whether an undesirable rearrangement to vitaletheine V4 is necessarily precluded by all salt complexes. It is clear from these concerns that over extrapolation of the therapeutic effects of one particular salt complex can be disastrous and that more formulation work is needed. These concerns are justified by the known toxicity and carcinogenicity of many common cations that have tenacious affinities for sulfur compounds such as lead, cadmium, and nickel. Since some of the vitaletheine modultors have been shown to have remarkable long-term potencies in the treatment of cancer in laboratory models, the carcinogenicity of the heavy metals may be explained, in part, by their abilities to disrupt the biochemical equilibriums of the vitaletheine modulators
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