Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Patent
1996-04-15
1998-08-04
Feisee, Lila
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
4241841, 4241981, 424479, 424488, 424493, 424499, 435 723, A01N 6300, A61K 3900, A61K 3938, A61K 936
Patent
active
057889643
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FI94/00333 which is a continuation of the U.S. application Ser. No. 08/103,519, filed Aug. 9, 1993, now abandoned.
BACKGROUND OF THE INVENTION
The invention relates to the treatment of cancer by sensitization of cancer cells by antiestrogens for lysis with killer cells, particularly with natural killer (NK) cells, lymphokine activated killer (LAK) cells and cytotoxic T lymphocytes (CTL).
The treatment of human cancer with autologous lymphokine activated killer (LAK) cells combined with recombinant-derived lymphokine, interleukin-2, has already been attempted with encouraging results (Rosenberg, 1987) as well as the treatment with activated cytotoxic T lymphocytes (CTL) (Fujimoto, 1992).
Nonsteroidal antiestrogens tamoxifen and toremifene belonging to the triphenylethylene class of compounds have gained wide therapeutic application for the treatment of estrogen receptor positive breast cancer. Tamoxifen and toremifene inhibit estrogen-induced growth by competitive antagonism of tumor estrogen receptors. Antiestrogen therapy is effective in prolonging a disease-free state and overall survival of women following primary surgery. Other well known triphenylethylene class antiestrogens are e.g. clomiphene and droloxifene (3-hydroxytamoxifen).
We have now discovered that estrogen receptor negative cancer cells are sensitized by triphenylethylene antiestrogens for lysis with NK, LAK and CTL effectors. This sensitization effect is thus not dependent on the presence of classical estrogen receptors. The use of the combination of antiestrogen treatment and killer cell therapy according to the invention is expected to significantly elevate the percentage of tumor remission and cure that has already been achieved by the above investigators with killer cells alone in a minor percentage of patients.
SUMMARY OF THE INVENTION
The invention relates to a method of sensitizing cancer cells for a killer cell mediated lysis which involves administering to a patient an effective amount of antiestrogen and killer cells either jointly or sequentially, wherein the killer cells are selected from the group of NK cells, LAK cells and CTL cells and the antiestrogen is selected from the group of triphenylethylene class antiestrogens, such as tamoxifen or toremifene or their pharmaceutically acceptable salt. Alternatively, killer cells may be induced in a host by one of known immunostimulation methods during the first treatment period and thereafter administering an effective amount of antiestrogen during the second treatment period.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a graph of a Winn assay with untreated, tamoxifen (TX) treated and toremifene (TO) treated P815 tumor cells.
FIGS. 2a, 2b and 2c are the survival curves for the experiment of FIG. 1.
FIG. 3 is a graph of the effect of oral TX and TO treatment alone or with LAK treatment on P815 tumor growth.
FIGS. 4a, 4b and 4c are the survival curves for the experiment of FIG. 3.
FIG. 5 is a graph of a winn assay with untreated, tamoxifen (TX) treated and toremifene (TO) treated P815 tumor cells.
FIGS. 6a, 6b and 6c are the survival curves for the experiment of FIG. 5.
FIG. 7 is a graph demonstrating the immunotherapy results of P815 mastocytoma with TX or TO and LAK cells.
FIGS. 8a, 8b and 8c are the survival curves for the experiment of FIG. 7.
FIG. 9 is a graph demonstrating the immunotherapy results of P815 mastocytoma with TX or TO given by gavage and LAK cells.
FIGS. 10a, 10b and 10c are the survival curves for the experiment of FIG. 9 .
DETAILED DESCRIPTION OF THE INVENTION
1. Detection of killer cells
The prerequisite for success of the treatment according to the invention is the presence of killer cells (e. g. NK, LAK or CTL) capable of destroying the patient's cancer cells in the body when the adjuvant therapy with an antiestrogen, e. g. tamoxifen (TX) or toremifene (TO), is initiated. Ideally, a suspension of cells would be prepared from the patient's tumor by digestion with collagenase as described by Freshney (1976) and used
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Baral Edward
Berczi Istvan
Kangas Lauri
Nagy Eva
Eyler Yvonne
Feisee Lila
Orion-yhtyma Oy
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