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While 1,25 dihydroxycholecalciferol (calcitriol) is best recognized for its effects on bone and mineral metabolism, epidemiological data indicate that low vitamin D levels may play a role in the genesis and progression of breast, lung, colorectal and prostate cancer, as well as malignant lymphoma and melanoma. Calcitriol has strong antiproliferative effects in prostate, breast, colorectal, head/neck and lung cancer, as well as lymphoma, leukemia and myeloma model systems. Antiproliferative effects are seen in vitro and in vivo. The mechanisms of these effects are associated with G0/G1 arrest, induction of apoptosis, differentiation and modulation of growth factor-mediated signaling in tumor cells. In addition to the direct effects on tumor cells, recent data strongly support the hypothesis that the stromal effects of vitamin D analogs (e.g., direct effects on tumor vasculature) are also important in the antiproliferative effects. Antitumor effects are seen in a wide variety of tumor types and there are few data to suggest that vitamin D-based approaches are more effective in any one tumor type. Glucocorticoids potentiate the antitumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. In addition, calcitriol potentiates the antitumor effects of many cytotoxic agents. Preclinical data indicate that maximal antitumor effects are seen with pharmacological doses of calcitriol and that such exposure can be safely achieved in animals using a high dose, intermittent schedule of administration. AUC and C(max) calcitriol concentrations of 32 ng.h/ml and 9.2 ng/ml are associated with striking antitumor effects in a murine squamous cell carcinoma model and there is increasing evidence from clinical trials that such exposures can be safely attained in patients. Another approach to maximizing intra-tumoral exposure to vitamin D analogs is to inhibit their catabolism. The data clearly indicate that agents which inhibit the major vitamin D catabolizing enzyme, CYP24 (24 hydroxylase), potentiate calcitriol killing of prostate tumor cells in vitro and in vivo. Phase I and II trials of calcitriol, either alone or in combination with carboplatin, taxanes or dexamethasone, as well as the non-specific CYP24 inhibitor, ketoconazole, have been initiated in patients with androgen-dependent and -independent prostate cancer and other advanced cancers. The data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered, but the optimal dose and schedule remain to be delineated. Clinical responses have been seen with the combination of high-dose calcitriol + dexamethasone in androgen-independent prostate cancer (AIPC) and, in a large randomized trial in men with AIPC, potentiation of the antitumor effects of docetaxel were seen.

Both adriamycin and daunomycin chelate Fe 3+ , forming complexes with similar spectroscopic properties but very different redox chemistry. Anaerobic Fe 3+ -adriamycin and Fe 3+ -daunomycin complexes of identical stoichiometry give rise to identical optical absorbance and EPR spectra with maxima at 600 nm and signals at g = 4.2 and g = 2.01. In anaerobic preparations, however, the 600 nm absorption band and the EPR signals of the Fe 3+ -adriamycin complexes decrease as Fe 3+ is reduced to Fe 2+ , with the appearance of an adriamycin free-radical signal at g = 2.0035, while the spectra of Fe 3+ -daunomycin complexes remain unchanged, with no free-radical signal appearing. Polarographic measurements demonstrate that the Fe 3+ -adriamycin complexes consume O 2 while the Fe 3+ -daunomycin complexes do not. Measurements in the presence of catalase and superoxide dismutase suggest that 75% of the O 2 consumed by Fe 3+ -adriamycin is reduced to H 2 O 2 or .O 2 − . Spin-trapping experiments demonstrate that the Fe 3+ -adriamycin complexes generate .OH, while the daunomycin complexes do not. Qunatitation of .OH generation by Fe 3+ -adriamycin demonstrates that the initital rate of .OH generation approaches the rate of total O 2 consumption. DNA cleavage studies show that only the Fe 3+ -adriamycin complexes cleave DNA in the absence of exogenous added H 2 O 2 . This DNA cleavage can be blocked by catalasa or .OH radical scavengers. These results indicate that the side-chain hydroxyl group is essential for Fe 3+ reduction, subsequent O 2 reduction, as well as for the generation of the drug free radical, since adriamycin and daunomycin are structurally identical except for this hydroxyl. The difference in redox chemistry of the iron complexes of adriamycin and daunomycin is the only known mechanism which can explain the difference in anti-tumor potency and cardiotoxicity of these two structurally similar drugs.