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ORAL ADMINISTRATION: Most oncology drugs are administered by i.v. infusion. We have the advantage with CZ48 in that it can also be administered orally. Oral administration has the distinct advantages of ease of administration, lower administration costs, and ease for the patient to self-dose at home. Oral dosing may also provide for lower overall toxicity compared to i.v. infusion. I.V. infusions are normally administered every one to three weeks per treatment cycle (21 – 28 days) with the entire dose administered over a few hours. In comparison, CZ48 will be administered daily for 28 days (with 5 days on drug followed by 2 days off). If during the treatment cycle laboratory values become out of range due to treatment, daily doses may simply be held for one or multiple days until the values become normal.
BLOOD BRAIN BARRIER: Many late stage cancer patients have brain metastasis. This is a particularly difficult problem as only a few drugs will pass the blood-brain barrier. Even these drugs have marginal effectiveness. Local administration of chemotherapy agents directly or indirectly to the brain are also marginally effective. Brain metastasis often times leads to the quick demise and death of the individual. The CPT based compounds that we are developing are small molecule drugs and as such are capable of passing the blood-brain barrier. Several studies have shown some measure of effectiveness in treating human cancers growing in the brain of nude mice with CPT based drugs. Much more work needs to be done in this area but these results are promising.
STEM CELLS: Pre-clinical data suggests that CPT based drugs are active against cancer stem cells. Cancer stem cells, compared to the bulk of the cancer cells which make up a tumor, are able to self-renew and differentiate into multiple cancer cell types. Cancer stem cells are known to be resistant to most treatment and are thought to be the main cause for relapse and metastasis. Most pre-clinical animal studies demonstrate drug efficacy by growth inhibition compared to untreated controls. This comparative reduction in mass demonstrates that at least one or more subpopulations of tumor cells are affective by the treatment. However, even with the reduction in tumor mass, the cancer stem cells may be totally unaffected. In treating human tumors in nude mice with CPT based drugs, the tumor mass many times is not only reduced, but completely eradicated. If treatment is stopped as soon as the tumor becomes un-measurable, the cancer will soon reform. It is thought that this process is due to the fact that the stem cells have not been killed. If however treatment is continued for a few weeks after the tumor is un-measurable, the tumor does not regrow. Even many months after treatment has been stopped, the tumor in these animals does not regrow. Although more work needs to be done in this area, this may demonstrate that the cancer stem cells have been eradicated.
LIMITED AND MANAGEABLE TOXICITY: Several of these CPT based drugs that have been used in humans display relatively little toxicity compared to traditional chemotherapy. Toxicity that has been seen in human use has always been reversible, causing no permanent injury to organs or tissues.
GOOD EFFICACY: One of the CPT drugs (9NitroCamptothecin) showed significant promise in a clinical study of 107 patients with advanced pancreatic cancer. Whereas average survival for pancreatic patients is less than 6 months from the time of diagnosis, in this study, approximately one third of the evaluable patients survived more than 12 months, and another third survived more than 18 months, with 11 of these patients surviving more than 24 months. Two of these patients were long term cures at 15+ years. Interim data for this study was published in the International Journal of Oncology. Topo Medtech believes that these type of results are just beginning as they unlock the full potential of Camptothecin based drugs.
ASSAY AND BIOMARKERS: The mechanism of action of Camptothecin based drugs is well understood. Using this knowledge, a biomarker will be developed to identify patients who will be responsive to a particular Camptothecin drug.
BLOOD BRAIN BARRIER: Many late stage cancer patients have brain metastasis. This is a particularly difficult problem as only a few drugs will pass the blood-brain barrier. Even these drugs have marginal effectiveness. Local administration of chemotherapy agents directly or indirectly to the brain are also marginally effective. Brain metastasis often times leads to the quick demise and death of the individual. The CPT based compounds that we are developing are small molecule drugs and as such are capable of passing the blood-brain barrier. Several studies have shown some measure of effectiveness in treating human cancers growing in the brain of nude mice with CPT based drugs. Much more work needs to be done in this area but these results are promising.
STEM CELLS: Pre-clinical data suggests that CPT based drugs are active against cancer stem cells. Cancer stem cells, compared to the bulk of the cancer cells which make up a tumor, are able to self-renew and differentiate into multiple cancer cell types. Cancer stem cells are known to be resistant to most treatment and are thought to be the main cause for relapse and metastasis. Most pre-clinical animal studies demonstrate drug efficacy by growth inhibition compared to untreated controls. This comparative reduction in mass demonstrates that at least one or more subpopulations of tumor cells are affective by the treatment. However, even with the reduction in tumor mass, the cancer stem cells may be totally unaffected. In treating human tumors in nude mice with CPT based drugs, the tumor mass many times is not only reduced, but completely eradicated. If treatment is stopped as soon as the tumor becomes un-measurable, the cancer will soon reform. It is thought that this process is due to the fact that the stem cells have not been killed. If however treatment is continued for a few weeks after the tumor is un-measurable, the tumor does not regrow. Even many months after treatment has been stopped, the tumor in these animals does not regrow. Although more work needs to be done in this area, this may demonstrate that the cancer stem cells have been eradicated.
LIMITED AND MANAGEABLE TOXICITY: Several of these CPT based drugs that have been used in humans display relatively little toxicity compared to traditional chemotherapy. Toxicity that has been seen in human use has always been reversible, causing no permanent injury to organs or tissues.
GOOD EFFICACY: One of the CPT drugs (9NitroCamptothecin) showed significant promise in a clinical study of 107 patients with advanced pancreatic cancer. Whereas average survival for pancreatic patients is less than 6 months from the time of diagnosis, in this study, approximately one third of the evaluable patients survived more than 12 months, and another third survived more than 18 months, with 11 of these patients surviving more than 24 months. Two of these patients were long term cures at 15+ years. Interim data for this study was published in the International Journal of Oncology. Topo Medtech believes that these type of results are just beginning as they unlock the full potential of Camptothecin based drugs.
ASSAY AND BIOMARKERS: The mechanism of action of Camptothecin based drugs is well understood. Using this knowledge, a biomarker will be developed to identify patients who will be responsive to a particular Camptothecin drug.