Theoretical basis and possible mechanisms

Our primary goal is providing the greatest possible benefit to each of our patients while also collecting relevant data on the use of this new treatment method.  As such, our clinical work follows the hypothesis that the combination of lovastatin and interferon is effective in the treatment of certain aggressive malignancies in a highly synergistic fashion.  A rich background of in vitro data portrays five or six interrelated effects of lovastatin and certain of its analogues on malignant cells.

The repeated finding that lovastatin has substantial activity against malignant cell lines while posing little known threat to normal ones suggests that the malignant cells employ an aberrant process or feature which can be targeted.  Such is the first mechanism:  many malignant cells are unusually dependent on de novo synthesis of cholesterol, especially of LDL composition, for growth and membrane integrity.  The dependence on the mevalonate pathway for the necessary supply explains the inability of the cells to grow and proliferate when this path is disabled.  Given sufficient continuous concentration of the drug over a period of time, apoptosis is induced in a number of malignant cell lines.  It is postulated that fragility of the membrane may leave the malignant cell susceptible to damage and death on its own or after exposure to other agents.  Therefore the effects may be cytostatic or cytocidal depending on dose and duration of exposure and characteristics of the individual cancer cell line.

The second observation is probably the most crucial and may increasingly be proven the root mechanism for several other anti-neoplastic effects.  Lovastatin and its analogues interfere with myriad post-translational protein processing reactions in the malignant cell, thus preventing critical proteins from being expressed on the membrane or in the nucleus.  Striking at such basic processes no doubt has the capacity to produce cytostasis or cellular death in many forms.  It is not understood why this doesn’t cause more discernible problems in normal cells, but it may be responsible for some of the side effects and we suspect this may be demonstrated with more time and research.

The third effect was recognized shortly after the discovery of compactin and lovastatin.  Cancer cells are prevented from completing mitosis in the presence of sufficient concentration of the hmg-CoA reductase inhibitors (HRIs), specifically in the G₀ or G₁ phases and between G₂ and M.  This cycle arrest is cytostatic only and in most cases can be reversed when the drug is withdrawn or mevalonate is added.  Future research may well reveal this to be due to specific defective proteins as mentioned above.

A fourth occurrence is closely related to the second and third phenomena discussed.  When a cell does initiate mitosis, lovastatin  interferes with DNA synthesis and more specifically prevents proper formation of daughter nuclei after DNA replication.  This may leave the nascent DNA exposed and “marked for destruction” in a cascade resulting in apoptosis and ultimately necrosis.

A fifth area of attack has been better characterized recently and carries profound implications.  Lovastatin has been shown both in vitro and in animal models to interfere significantly with the metastatic activity of a number of malignancies, usually by preventing adherence to and migration across endothelial surfaces.  This may be due to inhibition of the cell's ability to express certain membrane proteins necessary for this metastatic sequence.

Lovastatin has also been shown to impede tumor-induced angiogenesis in a melanoma model in mice, making it comparable in this respect to many other drugs now under intense study.  This action could be helpful in larger tumor masses but we do not believe the anti-neovascular effect, of itself, has potential for eradicating disease or preventing metastasis.  It seems more likely that other mechanisms are chiefly responsible for the observed benefits, coincident with but not directly due to impairment of angiogenesis.  These various agents may eventually prove to have much in common with the anti-neoplastic mechanisms of the HRIs.

Until recently the subject of interferon in melanoma and other malignancies has been a conundrum.  There seems little doubt that it has been of value to some individuals but the data are inconsistent among various experiences.  Overall, its value has been marginal even when statistically significant:  meta-analyses in melanoma confirm that, used alone, it confers a few extra months until relapse to about 15% of patients and no survival increase at all.  Since lovastatin administration in vitro can diminish natural killer (NK) cell cytotoxicity and interferon gamma production, Dr. Cantrell hypothesized in 2000 that concurrent exogenous interferon administration might be able to overcome any such down-regulation and in fact to enhance activity of the same cells in reverse fashion.  (This was admittedly a "shot in the dark" as no prior work suggested such a relationship.)  It is now apparent that the activity of interferon against malignant cells is primarily due to an enhanced effect of NK cells and/or other components of the native immune system.  It is further postulated that such activity is made more effective by impairment of the integrity of those cells due to the actions of lovastatin as described above, thus providing the needed signal for an immune reaction to suppress or even destroy cancerous cells.  The clinical and in vitro data to support or negate that hypothesis will emerge over the coming years, but the patient outcomes are already supporting the efficacy of the technique in a number of cancer types.