Cancer Therapy Toxicity Reduction

Method of Reducing the Toxicity of Anticancer Agents

U.S. Patent Number: 6,939,893
Date Issued: September 6, 2005

Summary: The invention discloses a method for enhancing the efficacy of anti-cancer agents. The method comprises administering to an individual, in need of such a treatment, an anticancer agent and a selenium compound. The selenium compounds may be administered before, during or after administration of the anti-cancer agent.

Detail: In the invention it was observed that administration of selenium compounds reduces the toxicity of anticancer agents. Data is presented for in vivo studies in two animal models. The invention discloses a method for reducing the toxicity of anticancer agents. The method comprises administering to an individual, in need of treatment, an anti-tumor agent and a selenium compound. The selenium compounds may be administered before, during or after administration of the anti-cancer agent. In one embodiment, the selenium compound is administered prior to chemotherapy and may be continued during and after the chemotherapy.

5-Amino-4-Imidazolecarboxamide Riboside as Potentiator of Antifolate Transport and Metabolism

U.S. Patent: Pending
Application Number: 11/327,872

Summary: The invention provides a method for increasing the efficacy of antifolates which act via inhibition of dihydrofolate reductase (DHFR). The method comprises the steps of administration of 5-amino-4-imidazolecarboxamide riboside (Z) or its base with the antifolate such that the targeted cells are exposed to both the antifolate and Z simultaneously. This results in increased influx of the antifolate. For MTX, accumulation of the more biologically active polyglutamate forms is also potentiated. This potentiation appears to be mediated by an effect on the RFC.

Detail: The invention provides a method for enhancing the uptake and efficacy of antifolates which act via inhibition of DHFR such as the 2,4 diaminopteridine antifolates methotrexate and aminopterin. The method is based on the unexpected observation that exogenous 5-amino-4-imidazolecarboxamide riboside (Z), a nucleoside precursor of (among others) the triphosphate ZTP, potentiates uptake of MTX and synthesis of MTX polyglutamate in cancer cells. Based on the data presented herein, it is considered that Z potentiates transport of antifolates via the RFC and the increased transport leads to increased synthesis of antifolate polyglutamates and consequently increased drug accumulation. Z was observed to enhance the growth inhibitory potency of MTX against cancer cells. Thus in one embodiment, this invention provides a method comprising the administration of Z or its base (i.e., 5-amino-4-imidazolecarboxamide) with an antifolate which acts via inhibition of the DHFR at concentrations at which the antifolate inhibits DHFR. The administration of Z or its base can be accomplished by any standard method, although systemic administration is preferred. Z has already been tested in clinical trials as a treatment for cardiac ischemia and is known to be nontoxic. In another embodiment, Z or its base and an antifolate which acts via inhibition of DHFR can be administered with a second antifolate(s) which primarily act via another mechanism such as inhibition of thymidylate synthase, inhibition of purine synthesis or other multi-targeted inhibition pathways. Administration of Z or its base with folate(s) which inhibit DHFR (with or without other folates) to enhance the efficacy of the folate(s) can be carried out for inhibiting the growth of cells as in various cancers as well as in other pathological conditions such as rheumatoid arthritis and psoriasis.

Tumor Necrosis Factor Inhibitory Protein Tip B1 and Method of Using Same

U.S. Patent Number: 6,197,744
Date Issued: March 6, 2001

Summary: A specific, unique, natural biological factor that has the capacity to abate one or more of the toxic effects of TNF. This factor may have therapeutic potential in one or more of the diverse disease states in which TNF is known to have a causative role. The unique, approximately 27 kDa protein is designated TIP-B.sub.1. TIP-B.sub.1, when purified and added back to TNF sensitive cells, effectively ablates TNF-induced cell lysis and TNFinduced apoptosis; cytolytic effects are central to many TNF-mediated actions. The invention includes a protein designated TIP-B.sub.1 purified to homogeneity. The protein has a molecular weight of about 27 kD. The protein is capable of inhibiting the action of TNF upon a cell, when said protein is introduced into extracellular medium surrounding the cell. The protein is free of sequences which interfere with normal cellular TNF binding sites and is free of sequences which directly bind to TNF. The invention further includes a method for using the protein for controlling TNF activity upon a cell.

Detail: This invention relates to the inhibition of the activity of tumor necrosis factor (TNF). TNF is known to have a causative role in many diseases such as chronic inflammation, certain types of arthritis, late stage wasting disease in cancer (cachexia), auto immune diseases such as lupus, and septic shock.

In accordance with the invention, a specific, unique, natural biological factor has been discovered that has the capacity to abate one or more of the toxic effects of TNF. This factor, therefore, may have therapeutic potential in one or more of the diverse disease states in which TNF is known to have a causative role. The unique, approximately 27 kDa protein is designated TIP-B.sub.1. TIP-B.sub.1, when purified and added back to TNF sensitive cells, effectively abates TNF-induced cell lysis and TNF-induced apoptosis; cytolytic effects are central to many TNF-mediated actions.

More particularly, the invention includes a protein designated TIP-B.sub.1 purified to homogeneity. The protein has a molecular weight of about 27 kD. The protein is capable of inhibiting the action of TNF upon a cell, when said protein is introduced into extracellular medium surrounding the cell. The protein is free of sequences which interfere with normal cellular TNF binding sites and is free of sequences which directly bind to TNF. The invention further includes a method for using the protein for controlling TNF activity upon a cell.

Method for Optimizing Cancer Therapy by Monitoring Maturation of Tumor Associated Vasculature by Selenium

Patent(s): Pending
U.S. Patent Application Number: 11/728,075

Summary: This invention provides a method for a method for optimizing the regimen for the administration of chemotherapeutic agents. The method comprises administration of a selenium compound to an individual, monitoring the modulation of tumor vessel maturation (TVM) to identify an optimal time for administration of a chemotherapeutic agent. This invention also provides a method to determine whether or not a tumor is likely to be a responder to chemotherapy. The method comprises administration of a selenium compound to an individual and determining whether or not an increase in TVM is observed. An increased TVM following administration of selenium is an indi- cation that the tumor will likely respond the chemotherapy.

Detail: The present invention provides a method for optimizing the regimen for the administration of chemotherapeutic agents. The method is based on the observation that selenium compounds such as methylselenocysteine (MSC) and seleno-L-methionine (SLM) enhance the maturation of existing tumor blood vessels while inhibiting the development of new blood vessels. Accordingly, the method comprises administration of a selenium compound to an individual, monitoring the modulation of tumor vessel maturation (TVM) to identify an optimal time for administration of a chemotherapeutic agent. In another embodiment, a method is also provided to determine whether or not a tumor is likely to be a responder to chemotherapy. This method comprises the steps of administration of a selenium compound to an individual and determining whether or not an increase in TVM is observed. An increased TVM following administration of selenium is an indication that the tumor will likely respond to the chemotherapy.

Method of Reducing Alopecia and Bladder Toxicity of Cyclophosphamide

Patent(s): Issued
U.S. Patent Number: 7,534,818
Date Issued: May 19, 2009

Summary: The present invention discloses a method for reducing alopecia and bladder toxicity associated with the anti-cancer agent cyclophosphamide. The method comprises administering to an individual, in need of such a treatment, cyclophosphamide and a selenium compound. The selenium compounds may be administered before, during or after administration of the anti-cancer agent.

Detail: In the present invention it was observed that administration of selenium compounds reduces toxicity associated with administration of cyclophosphamide. Cyclophosphamide induced toxicity includes weight loss, alopecia and bladder toxicity. Data is presented for in vivo studies using an animal model. Accordingly, the present invention discloses a method for reducing toxicity of cyclophosphamide including alopecia and bladder toxicity. The method comprises administering to an individual, in need of treatment, cyclophosphamide and a selenium compound. The selenium compounds may be administered before, during or after administration of the anti-cancer agent. In one embodiment, the selenium compound is administered prior to chemotherapy and may be continued during and after the chemotherapy.