Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-11-16
2002-11-26
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S651000
Reexamination Certificate
active
06486146
ABSTRACT:
BACKGROUND-SUMMARY
Prior art has used endocrine downregulation therapy to downregulate the growth of endocrine dependent cancers. Present invention takes exactly the opposite approach, using endocrine upregulation to accelerate the growth of cancer in conjunction with administration of phase specific chemotherapeutics to increase tumor kill rates and reduce systemic toxicity over prior art.
Additionally, prior art has been unable to achieve high cure rates using phase specific chemotherapeutics in non endocrine dependent metastatic cancers as well. Applicant has discovered that the primary reason is prior art's failure to adjust the chemotherapeutic administration intervals for cancer's accelerated growth rate over successive chemotherapeutic administrations. This failure results in the cancer's return to an asynchronously cycling population which is mathematically a catastrophic event in the context of a phase specific administration regimen. Accordingly, applicant has disclosed methods for computing variable administration intervals that will keep the phase specific chemotherapeutic synchronized with the susceptible phase in the target cancer population. Alternatively, applicant has also disclosed methods of modulating the growth rate of endocrine dependent tumors by using endocrine hormones so as to keep a target cell population synchronized to a given administration regimen.
Definitions
As used in this application, the term “endocrine dependent cancer(s)” is used to mean cancers that have retained the functional hormone receptors normally present in the underlying tissue from which they arose and whereby cancer cells possessing these receptors will respond to administration of exogenous hormones by upregulating DNA synthesis. Examples of hormone receptors include, but are not limited to, estrogen receptors, progesterone receptors, and testosterone receptors.
BACKGROUND
Harrison's Principles of Internal Medicine (14th ed. p. 527-536) categorizes prior art drug treatments used for cancer into four broad categories Chemotherapy, Endocrine Therapy, Immunotherapy, and Hematopoietic Growth Factors. Chemotherapy relates to substances toxic to cancer. Endocrine Therapy relates to inactivating or inhibiting steroids produced by the body that promote growth of certain cancers. Immunotherapy relates to enhancing various aspects of the natural human immune system to inhibit growth of cancer. Hematopoietic Growth Factors focus on enhancing recovery of bone marrow products for patients receiving myelosuppressive chemotherapy. Chemotherapy and Endocrine therapy have relevance to present invention and as such a brief background of prior art is provided.
Prior Art Chemotherapeutics (HPIM 14th ed. pgs. 527-534)
Most chemotherapeutic agents in use today are cell cycle active; that is, they are cytotoxic mainly to actively cycling cells. In addition, some cell cycle active agents are phase specific; that is, they are cytotoxic to cells in a particular phase of the cell cycle.
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. These agents are best regarded as cell-cycle active but non-phase specific.
Purine/pyrimidine analogs/antimetabolites induce cytotoxicity by serving as false substrates in biochemical pathways. They are cell cycle active and specific mainly for the S phase. 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. They are cell cycle active and cytotoxic predominately during the M phase of the cell cycle.
Antitumor Antibiotics include bleomycin that induces DNA strand breakage through free radical generation and Mitomycin C which cross links DNA. They are cytotoxic mainly during the G2 and M phase.
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.
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, such as alkylating agents, 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, such as the antimetabolites, 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 (HPIM 14th ed. 527-528 Pharmocodynamics section).
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 (see HPIM 14th ed. P. 528, FIGS. 86-3 enclosed). 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. The usefulness of many chemotherapeutics is limited by the fact that they have a narrow therapeutic index (HPIM 14th ed. p.527).
Tumor regression in response to chemotherapy is logarithmic. A given dose of chemotherapy kills a constant percentage of cells. The “cell kill rate” (CKR) as used in this application is hereby defined as the percentage of cells that are killed during one cell division cycle at a given dosage of chemotherapeutic. The “tumor kill rate” as used in this application is hereby defined as the percentage of cells of a tumor that are killed during one administration cycle of a chemotherapeutic, which is directly proportional to the CKR and the number of cell division cycles that occur over the chemotherapeutic's administration (or efficacy) period. As an example, if a 90% CKR chemo is administered over one cell division cycle, the tumor kill rate is also 90%. If the 90% CKR is administered over two cell division cycles the tumor kill rate is 99%. Conventional methods typically focus on “maximum tolerated doses” and extended administration periods.
Cyclical administration is required to allow normal rapidly proliferating cell populations to recover from the effects of chemotherapy. 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. As an
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