Reference is hereby made to co-pending Ser. No. 06/916,008, filed Oct. 6, 1986, now allowed; Ser. No. 06/871,120, filed June 5, 1986, now U.S. Pat. No. 4,800,031; Ser. No. 06/944,301, filed Dec. 19, 1986, now U.S. Pat. No. 4,849,412; Ser. No. 07/002,981, filed Jan. 13, 1987, now U.S. Pat. No. 4,782,065. The disclosures of the foregoing are also herein incorporated by reference.
1. Field of the Invention
The present invention relates to novel methods for the treatment of neoplastic conditions through administration of calcium flux blockers of the papaverine family in combination with one or more of the interferons. The present invention also relates to pharmaceutical compositions which include the combination of an effective concentration of a papaverine family agent in combination with one or more of the interferons.
2. Description of the Related Art
Neoplastic and hyperplastic disorders constitute a major health problem in the world today, with relatively few antineoplastic agents having the desirable properties of both efficacy and reduced toxicity. In fact, the vast majority of antitumor agents currently in use are generally both relatively non-tumor specific, as well as highly toxic to the patient being treated. For example, typical toxicities associated with antitumor therapy include depression or even destruction of bone marrow, gastro intestinal tract cells, or any of a host of other "normal" cells having higher than average growth rates.
Biological compounds such as cytokines, lymphokines and the like have been identified which exhibit some degree of antitumor or antiproliferative actions. These biological compounds tend to offer the advantage of a somewhat reduced overall toxicity and, in general, most biological anticellular agents are fairly well tolerated at therapeutically employed dose levels. For example, the principle side affects associated with interferon therapy, whether it be therapy using alpha, beta, gamma interferon, or a mixture of these, are the so-called "constitutional" symptoms of fever, chill, myalgias, headaches, malaise and the like. Moreover, agents such as tumor necrosis factor (TNF), lymphotoxin and related cytokines tend to exhibit similar side effects. This is not to mean that all biologicals are free of toxicity problems. For example, a fairly significant toxicity has been ascribed to biologicals such as interleukin-2 (IL-2) which are employed to activate killer cells, e.g., by adoptive immunotherapy.
Unfortunately, while biologicals such as the interferons tend to exhibit generally acceptable toxicity levels, they often tend to be hampered by an overall low antiproliferative potency. Moreover, while agents such as the interferons, for example, tend to exhibit relatively mild side effects on the whole, these side effects are, nevertheless, often both dose-dependent and dose-limiting. Thus, there is a practical limit to how much drug can be administered in order to achieve a desired antiproliferative affect. Accordingly, there is currently a great need for methods or other agents which can be employed to improve the potency of biologicals such as interferon without, of course, introducing any of their own additional toxicities.
In U.S. Pat. No. 4,663,317, as well as the co-pending applications listed above, it is demonstrated that certain classes of smooth muscle relaxing agents tend to exhibit profound, clinically significant antiviral activity. These smooth muscle relaxing agents are characterized functionally in terms of their action as calcium influx blockers, intracellular calcium flux inhibitors and/or cyclic nucleotide modulators. Moreover, it has been found that agents from one of the foregoing groups tend to exhibit synergistic activity when employed in combination with agents from another of the foregoing groups.
Probably the most significant single antiviral agent of the foregoing smooth muscle relaxers is papaverine and its various antivirally active congeners defined as those papaverine family agents having an intact isoquinoline ring structure, for example, as described in Ser. No. 06/944,301. These papaverine family members (isoquinoline ring congeners) tend to exhibit truly surprising antiviral activity, particularly in the treatment of human cytomegalovirus (HCMV) infections. However, there is no suggestion from these or any related disclosures known to the present inventors which would tend to suggest the usefulness of the papaverine family agents in combination with the interferons, whether alpha, beta, gamma or mixtures thereof, in the treatment of neoplastic or hyperplastic conditions or disorders.
However, it has now been discovered that not only are the papaverine agents useful as antivirals, but unexpectedly, they have proven to function synergistically with interferons to dramatically enhance the antiproliferative, as well as the antiviral, actions of the interferons.