Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
2000-03-03
2002-07-16
Caputa, Anthony C. (Department: 1642)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C424S009100, C435S004000, C435S069100
Reexamination Certificate
active
06419896
ABSTRACT:
BACKGROUND OF THE INVENTION
There is no tool more essential to cancer research than the experimental tumor. Every therapeutic and preventative strategy employs such tumors, and tumors growing in animals are instrumental to basic studies of cancer biology. Many experimental tumors are injected subcutaneously because subsequent growth can be followed visually. However, it is often preferable to have tumors grow internally. Such internal growths more closely mimic the environment of naturally occurring tumors, because host factors (blood supply, immune recognition and destruction, extracellular matrix, etc.) are far different at internal sites than in the skin. Metastasis, a defining feature of malignancy, cannot be assessed through observation of the skin. Moreover, the size of subcutaneous tumors often does not reflect the true tumor load, as the volume composed of stroma, necrosis, and scar tissue cannot be distinguished from that occupied by neoplastic cells.
For these reasons, internal tumors have also been widely used for studies of tumor biology. However, the presence of internal tumors is generally apparent only when symptoms develop, which generally occurs quite late during tumorigenesis. Surgical approaches to detect smaller internal tumors can be useful, but anesthetics and surgical manipulation can disturb the natural course of tumorigenesis and introduce other variables into the analysis. Human lactic dehydrogenase and &agr;-1-antitrypsin have been proposed as serum markers in xenograft-nude mice tumor models. However, the repetitive anesthesia and blood collections required for these approaches have hampered their widespread use.
In addition, mice with internal tumors are generally sacrificed at the end of an experimental protocol to determine how the tumors have responded. Only a single time point can be assessed using this approach, and multiple mice must be studied to minimize the effects of tumor and host heterogeneity. Imaging techniques provide a way of following tumor growth in situ, but are only applicable to rather large tumors.
To overcome the problems noted above, there is a need in the art for a system for monitoring internal tumor growth that would (i) provide a quantitative measure of neoplastic cell content, (ii) be cost-effective and simple to implement, and (iii) be broadly applicable to diverse tumor types and hosts.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a method for monitoring growth of an experimentally induced tumor within an animal body.
It is another object of the present invention to provide a device for collecting urine from a small mammal.
It is another object of the present invention to provide a method for collecting urine from a small mammal.
These and other objects of the invention are provided by one or more of the embodiments described below.
One embodiment of the invention provides a method for monitoring growth of tumor cells within an animal body. A recombinant tumor cell which comprises an expression construct encoding a secretable exogenous marker protein is administered to an animal. Urine is collected from the animal and secretable exogenous marker protein in the urine is measured. Secretable exogenous marker protein in the urine is proportional to the number of viable tumor cells in the animal.
Another embodiment of the invention provides a device for collecting urine from a small mammal. The device has a floor comprising a plurality of liquid-impermeable wells for deposition of urine by a small mammal. The device also has one or more walls enclosing at least a portion of the plurality of wells. The walls of the device are of sufficient height to inhibit or prevent escape of the small mammal. The floor of the device comprises sufficient wells within the walls so that at least 50% of the wells which are occupied by urine are not also occupied by feces after a period of time sufficient for 90% of a population of healthy said small mammals to have urinated.
Yet another embodiment of the invention provides another device for collecting urine from a small mammal. The device has a floor comprising a plurality of liquid-impermeable wells for deposition of urine by a small mammal. The device also has one or more walls enclosing at least a portion of the plurality of wells. A small mammal is on the floor and within the walls. The walls of the device are of sufficient height to inhibit or prevent escape of the small mammal.
Still another embodiment of the invention provides a method for collecting urine from a small mammal. A small mammal is placed in a device comprising a floor and one or more walls. The floor of the device comprises a plurality of liquid-impermeable wells for deposition of urine by a small mammal and one or more walls enclosing at least a portion of the plurality of wells. The walls of the device are of sufficient height to inhibit or prevent escape of the small mammal.
The invention thus provides the art with non-invasive methods and devices for frequently monitoring a biochemical marker in the urine of experimental animals.
REFERENCES:
Coimbra et al. (Braz.J.Med.Biol.Res., vol. 17, 1984).*
Urnovitz et al. (Trends Biotech.Sci., vol. 14, 1996).*
Iles et al. (Prenat Diagn., vol. 18, 1998, abstract only).*
Marini et al. “Assessment of bystander effect potency produced by instratumoral implantation of HSVtk-expressing cells using surrogate marker secretion to monitor tumor growth kinetics” Gene Therapy (1995) 2, 665-659.
Pesce et al. “Human Lactic Dehydrogenase as a Marker for Human Tumor Cells Grown in Athymic Mice” Cancer Research 37, 1998-2003, Jul. 1977.
Kinzler Kenneth W.
Shih le-Ming
Vogelstein Bert
Banner & Witcoff , Ltd.
Caputa Anthony C.
Nickol Gary B.
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