Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-30
2002-01-29
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S450000, C514S452000, C514S453000, C514S456000, C514S460000, C514S475000, C604S187000
Reexamination Certificate
active
06342520
ABSTRACT:
BACKGROUND—SUMMARY
Certain Sesquiterpenoid compounds (macrocyclic trichothecenes) and methods for using such compounds to inhibit proliferation of malignant cells without inducing appreciable systemic cytotoxicity are disclosed. The compositions and methods presented also greatly reduce the duration of administration regimens compared to prior art and provide novel synergistic uses in combination with prior art chemotherapeutics.
BACKGROUND
Prior Art Chemotherapeutics (HPIM pits. 527-534)
Most chemotherapeutic agents in use today are cell cycle active; that is, they are cytotoxic mainly to actively cycling cells. Alkylating agents are among the most widely used anti tumor agents and are efficient at cross-linking DNA, leading to strand breakage. Alkylating agents include cyclophosphamide, ifosfamide, melphalan, busulfan, mechlorethamine (nitrogen mustard), chlorambucil, thiotepa, carmustine, lomustine as well as platinum compounds such as cisplatin and carboplatin, which are not true alkylating agents also lead to covalent cross linking of DNA. Purine/pyrimidine analogs/antimetabolites induce cytotoxicity by serving as false substrates in biochemical pathways. They include cytarabine, fluorouracil, gemcitabine, cladribine, fludarabine, pentostatin, hydroxyurea, and methotrexate. Topoisomerase inhibitors interfere with the enzymes topoisomerase 1 and topoisomerase 2, responsible for mediating conformational and topological changes in the DNA required during transcription and replication. These agents include daunorubicin, doxorubicin, idarubicin, etoposide, teniposide, dactinomycin, and mitoxantrone. Plant Alkaloids include vincristine, vinblastine, and vinorelbine which inhibit microtubule assembly by binding to tubulin and docetaxel and paclitaxel which function by stabilizing microtubules and preventing their disassembly. Antitumor Antibiotics include bleomycin that induces DNA strand breakage through free radical generation and Mitomycin C which cross links DNA. Other Agents include dacarbazine and procarbazine which act as alkylating agents to damage DNA and L-Asparaginase, the only enzyme used as a anti tumor agent, which acts by depletion of extracellular pools of asparagine.
Prior art chemotherapeutics typically work by one highly specific pathway to damage or prevent DNA replication. Compositions of present invention work by several pathways that have direct, indirect, and synergistic effects against cancer (discussed later in the application).
Principles of Chemotherapeutic Administration (HPIM pgs. 527-528)
Chemotherapeutic agents exhibit a dose response effect. At sufficiently low concentrations no cytotoxicity is observed. At increasing concentrations, cell kill is proportional to drug exposure. At high concentrations, the effect reaches a plateau. Drugs that are cell cycle active, but not phase specific, characteristically have steep dose response curves: An increase in the drug concentration by an order of magnitude or more results in a proportional increase in tumor cell kill. By contrast, the dose response curve of phase specific agents typically is linear over only a narrow range. These agents are less suitable for dose escalation and increased tumor cell kill is observed after prolonged exposure as a larger percentage of the tumor cells enter the cell cycle.
Chemotherapy employs two principles in administration: Therapeutic Index Dosaging and Cyclical Administration. The therapeutic index represents the difference between the response of the tumor and response of normal tissue for a given dose of chemotherapeutic. Normal cells are also susceptible to the cytotoxic effects of chemotherapeutic drugs and exhibit a dose-response effect, but the response curve is shifted relative to that of malignant cells (HPIM p. 528, FIG. 86-3). This difference represents the therapeutic index. The toxicity to normal tissue that limits further dose escalation is the “dose-limiting toxicity”. The dose just below this point is the “maximum tolerated dose”. Proliferative normal tissues such as the bone marrow and gastrointestinal mucosa are generally the most susceptible to chemotherapy-induced toxicity.
Cyclical administration is used to allow normal rapidly proliferating tissue such as hemopoietic stem cells to recover and blood counts to reach their normal levels. Most chemotherapeutics are administered in cycles of 21 to 28 days and 6 to 8 cycles are typically used. The number of administration cycles required to completely eradicate a tumor is dependent on the tumor kill rate of the therapeutic. To completely eradicate a tumor it is necessary to get below the mathematical 1 surviving cell number (“log cell kill model” developed by Skipper and coworkers, described in HPIM p. 527, and incorporated herein by reference). As an example, to kill a 10 billion cell tumor with a chemotherapeutic that kills 95% of the tumor cells each administration cycle (5% survive) would require 8 cycles of chemotherapy (i.e. 10,000,000,000×0.05×0.05×0.05×0.05×0.05×0.05×0.05×0.05=0.39). However, this assumes the tumor does not grow in the period when the chemotherapeutic is not administered (“off” period).
Administration methods for therapeutics of present invention, for cytotoxic activity against target cancer cell populations, vary radically from prior art in that therapeutics of present invention are not administered into general circulation but administered interstitially at the tumor site. Although compositions of current invention are cell cycle active, because they are administered interstitially and rapidly internalize into cells, they do not induce the systemic cytotoxicity of prior art chemotherapeutics.
Current Invention as Measured by Prior Art Standards Against Prior Art Chemotherapeutics
Under prior art standards, the larger the therapeutic index between cytotoxicity to tumors versus normal tissue the “better” a chemotherapeutic was, as it has greater specificity to the cancer cells (HPIM p. 528 FIG. 86-3). The “normal tissue response” line for computation of therapeutic index as defined by prior art however, is the most susceptible or rapidly proliferating normal tissue in the body that the chemotherapeutic reached—and that would normally be cells in the bone marrow. There are roughly 210 different types of epithelial cells in the body and when using systemic administration methods as in prior art, there are theoretically ~210 “normal tissue response” curves that exist, with only the leftmost one (e.g. bone marrow) considered for therapeutic index computation.
Because therapeutics of current invention are administered substantially interstitially and localized, the “normal tissue response” curve for computing therapeutic index is based on the surrounding tissue into which it is injected (e.g into breast, lung, brain, etc . . . ) which is not normally a rapidly proliferating tissue and by definition would be situated well to the right of the comparable bone marrow or gastrointestinal mucosa lines. Present invention thus limits the theoretical number of potential response lines to a very small subset of the ~210 possible cell types, eliminating the known “far left” normal response curves of cell types such as bone marrow or gastrointestinal mucosa. Thus, the therapeutic index would be much larger for compositions of present invention simply because the “normal tissue response” line would be shifted over to the right, increasing the therapeutic index gap, making compositions of present invention “better” under prior art standards.
Trichothecenes
Fungi of the genera Fusarium, Myrotecium, Trichoderma, Stachybotrys and others produce Trichothecene mycotoxins. Trichothecenes constitute a family of fungal sesquiterpene epoxides that inhibit protein synthesis. Trichothecene mycotoxins are low molecular weight (250-700 daltons), non volatile compounds, and of over 150 trichothecenes have been identified. There are two broad classes: those that have only a central Sesquiterpenoid structure and those that have an additional macrocyclic ring
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