Page 7 - Vitamin D and Cancer

vi Preface

(c) Direct comparisons of toxicity and antitumor efficacy of analogues and parent
compound (calcitriol) using the apparently most active drug schedules
Unfortunately, for vitamin D based studies in cancer, very little of this rudimentary
work has been carried out. Studies with most analogues of vitamin D (paricalcitol,
seocalcitol, inecalcitol) have employed continuous dosing schedules even though
practically all in vitro and in vivo studies which have shown anticancer activity of
vitamin D have exposed cells and tumors to intermittent, high-pulse doses. Many
have been encouraged by the study of daily dosing of analogues and parent com-
pound (calcitriol) and finding the analogue causes less hypercalcemia. Often and
not surprisingly, the analogue binds less avidly to VDR. Such studies have led to
small to medium sized studies using daily dosing algorithms which have shown no
antitumor effects and been halted without any toxicity remotely resembling those
defensible in patients with advanced cancer.
Further limiting work with calcitriol has been the absence of a formulation suit-
able for high-dose therapy. This limitation is due primarily to the lack of an eco-
nomic motivation for the development of such formulations.
The following chapters provide excellent and comprehensive discussions of the
potential role of vitamin D based therapies in breast, colorectal, prostate cancer, and
leukemia and myelodysplastic syndromes. These chapters also point out that the
focus on these diseases is largely determined by the interests and expertise of the
outstanding scientists who have chosen to pursue vitamin D based cancer therapeu-
tics. To our knowledge, every tumor type ever evaluated has shown some biochemi-
cal and antiproliferative response to vitamin D. Similarly, vitamin D analogues,
especially calcitriol, potentiate almost every cytotoxic agent with which combina-
tion therapies have been tested. In our view the slow and halting development of
vitamin D based cancer therapeutics could be greatly accelerated by following
standard principles of anticancer drug development:
(a) Development of a standardized formula.
(b) Determination of MTD (current data indicate the MTD of calcitriol on an inter-
mittent [weekly] schedule is ³100 mcg). No reliable oral MTD have ever been
determined and few data on the optimal biologic dose developed in the labora-
tory, much less in the clinic.
(c) Conduct of carefully designed clinical trials.
The field of vitamin D based cancer therapeutics has very few such data items avail-
able. Perhaps the extensive preclinical data on the antitumor effectiveness of high-
dose vitamin D analogue therapy are misleading or in fact wrong. But until the
agent is examined in the fashion one would follow for an antineoplastic – we will
never know. The following chapters point out what is known and the direction that
can be followed in clinical development of vitamin D as an anticancer agent.

Buffalo, NY Donald L. Trump
Buffalo, NY Candace S. Johnson