Agent for treating papilloma virus-positive malignant and premalignant lesions

The present invention relates to a preparation comprising a substance influencing the cellular redox state for treating papilloma virus-positive malignant lesions.

This is a national phase filing of the Application No. PCT/DE95/01395,
 which was filed with the Patent Corporation Treaty on Oct. 5, 1995, and is
 entitled to priority of the German Patent Application P 44 35 661.7 filed
 Oct. 5, 1994.
 I. FIELD OF THE INVENTION
 The present invention relates to the use of a preparation comprising a
 substance influencing the cellular redox state for treating papilloma
 virus-positive malignant and premalignant lesions.
 II. BACKGROUND OF THE INVENTION
 It is well known to treat lesions which are caused by human-pathogenic
 papilloma viruses (HPV) by the application of cytokines, such as
 .alpha.-tumor necrosis factor and interferons. For this purpose, cytokines
 are administered in high doses. The treatment of patients exposed to high
 cytokine doses is accompanied by considerable side-effects such as
 cachexia, queasiness, vomiting and headache.
 Therefore, it is the object of the present invention to provide a
 preparation for treating papilloma virus-positive malignant and
 premalignant lesions, by which the above side-effects are reduced.
 According to the invention this is achieved by using a preparation
 comprising a substance influencing the cellular redox state.
 III. SUMMARY OF THE INVENTION
 The present invention relates to a preparation comprising a substance
 influencing the cellular redox state for treating papilloma virus-positive
 malignant lesions.
 IV. DETAILED DESCRIPTION OF THE INVENTION
 The expression "a substance influencing the cellular redox state" comprises
 compounds of any kind which can reduce the redox state of cells,
 particularly of host cells of papilloma viruses. They may be, e.g.,
 exogenous compounds. Examples of the above compounds are antioxidants such
 as pyrrolidine-dithiocarbamate (PDTC) and derivatives thereof. The
 compounds included in the preparation used according to the invention may
 also be metabolized into the actual substance influencing the cellular
 redox state as late as in the cell to be treated.
 The preparations used according to the invention may also contain several
 of the substances.
 In order for the modulator substance to display its effect, it has to be
 both intracellularly and extracellularly sufficiently stable within the
 body, i.e., it may not be metabolized to give an ineffective compound
 before it has displayed its effect. A person skilled in the art knows
 which factors influence the stability. Moreover, he knows for how long a
 compound has to be stable to display its effect. In addition, he is
 familiar with tests of how to determine the stability of the compounds.
 In a preferred embodiment, the preparation also includes a cytokine.
 Examples thereof are interferons and .alpha.-tumor necrosis factor
 (TNF-.alpha.). Recombinant interferon and recombinant .alpha.-TNF are used
 preferably. The cytokine dose administered with the preparations used
 according to the invention is lower than the cytokine dose administered so
 far. Thus, the positive effect of cytokines can be achieved by the
 preparation used according to the invention without resulting in the above
 drawbacks thereof. The effect of the substance influencing the cellular
 redox state is also increased when a cytokine is present.
 Conjugates according to the invention distinguish themselves in that they
 have little side-effects. Thus, they are suited in the best possible way
 for the treatment of papilloma virus-positive, particularly HPV-positive,
 malignant and premalignant lesions such as carcinomas of the genital zone.
 This also includes warts.
 The below examples explain the invention in more detail. The following
 preparations and examples are given to enable those skilled in the art to
 more clearly understand and to practice the present invention. The present
 invention, however, is not limited in scope by the exemplified
 embodiments, which are intended as illustrations of single aspects of the
 invention only, and methods which are functionally equivalent are within
 the scope of the invention. Indeed, various modifications of the invention
 in addition to those described herein will become apparent to those
 skilled in the art from the foregoing description. Such modifications are
 intended to fall within the scope of the appended claims.

V. EXAMPLES
 A. Example 1
 Reduction of HPV 18 Transcription by PDTC
 HPV-positive cells (DEM medium 10% fetal calf serum (BRL), 1%
 penicillin/streptomycin) are incubated with PDTC (from Sigma, dissolved in
 serum-free DEM medium directly before the start of the experiment; final
 concentration: 100 .mu.M) under conventional conditions. About 70%
 reduction of the HPV 18 transcription occurs after 6 hours (assay
 technique: conventional "Northern" blot analysis). The reduction of the
 HPV 18 transcription is an indicator of the reduced cell growth of the
 HPV-positive cells and thus also of the therapeutic effectiveness.
 B. Example 2
 Suppression of the HPV 18 (Specific RNA) Transcription by a Combination of
 PDTC and TNF-.alpha.
 Non-tumorous cell hybrids between HPV 18-positive cervical carcinoma cells
 (HeLa) and human fibroblasts are incubated with 100 to 150 units/ml
 TNF-.alpha. and 100 .mu.M PDTC. The RNA is extracted after 12 to 14 hours.
 An almost complete suppression of the HPV 18 transcription results under
 these conditions.
 If TNF-.alpha. is used alone, the same suppression effect can be observed
 with about 500 units/ml TNF-.alpha..
 As follows from the above results, the TNF-.alpha. dose can be reduced as
 compared the sole administration of TNF-.alpha. by simultaneous
 administration of PDTC and TNF-.alpha., with the same effect being
 obtained.
 All references cited within the body of the instant specification are
 hereby incorporated by reference in their entirety.