WO1993021939A1

WO1993021939A1 - Method of treating cancer

Info

Publication number: WO1993021939A1
Application number: PCT/US1993/003178
Authority: WO
Inventors: Bruce R. Bistrian
Original assignee: New England Deaconess Hospital Corporation
Priority date: 1992-04-27
Filing date: 1993-04-05
Publication date: 1993-11-11
Also published as: AU3973793A

Abstract

The combination of total parenteral nutrition (TPN) and Insulin-like Growth Factor-1 (IGF-1) has significant beneficial effects in the treatment of cancer. While either TPN or IGF-1 alone can cause deleterious effects in terms of increasing tumor growth rate, the combination therapy provides better patient nutrition while minimizing tumor growth rate.

Description

METHOD OF TREATING CANCER

* Background of the Invention

* The present invention concerns novel treatments for a variety of cancers, particularly sarcomas and carcinomas. Specifically, the methods and diet of the present invention use a combination of two known therapies which independently promote protein metabolism. While promotion of protein metabolism is beneficial in most patients, it is deleterious in cancer patients because it preferentially promotes tumor growth. Surprisingly, the combination of these two treatments, Insulin-Like Growth Factor-1 (IGF-1) and total parenteral nutrition (TPN) , provide the expected benefits to the patient as a whole while not causing excess tumor growth and in some circumstances even reducing tumor growth.

One of the problems in many disease states is providing adequate nutrition for the patient. Most forms of cancer aggravate this problem since providing adequate nutrition to the patient as a whole provides the rapidly proliferating cells of the cancer with the nutrients needed to reproduce even more rapidly. Accordingly, promoting the well-being of the patient while not aggravating the underlying causes of the disease, the proliferation of the cancer, can be exceptionally difficult.

However, in order to treat the cancer, the life and well-being of the patient must be maintained. For this reason, TPN is often used in the treatment of cancerous patients, particularly those undergoing chemotherapy or who are in an advanced state of cancer. TPN is often necessary to counteract the cachexic state that develops in many forms of cancer. United States Patent No. 4,906,664, assigned to New England Deaconess Hospital Corporation, discusses the treatment of cancer cachexia with a particular class of structured lipids, those having both medium chain fatty acids and ω-3 long chain fatty acids on the same glycerol backbone. The same structured lipid described in United States Patent No. 4,906,664 for treatment of cancer cachexia was also found to be an effective treatment for the underlying sarcomas. See United States Patent No. 5,081,105, also assigned to New England Deaconess Hospital Corporation. Other materials which have been discussed as possible nutritional support additives for use in cancer treatment include xylitol and branched-chain amino acids. See "Some practical and theoretic concepts in the nutritional assessment of the cancer patient", B. Bistrian, Cancer. 58(8), 1863-1866 (1986). This article discusses some parallels between cachexic and- other malnutrition states found in certain cancers and semistarvation and the severe metabolic response to infection and injury.

The effect of IGF-1 in the treatment of hypercatabolism and metabolic stress has also been published previously. IGF-1 has a strong anabolic effect on muscle, causing suppression of protein degradation, increased amino acid uptake, and cellular proliferation. See "Role of exogenous growth hormone and insulin-like growth factor-1 in malnutrition and acute metabolic stress: A hypothesis", W. Chwals and B. Bistrian, Critical Care Medicine 19(10). 1337-1322 (1991). In this article, one of the present inventors discusses the effects of IGF-1 in hypercatabolic states. IGF-1 has shown many of the same positive effects as TPN in preserving or elevating protein levels, causing increases in weight gain, decreases in protein breakdown, and increases in amino acid incorporation in liver and muscle protein.

Because both TPN and IGF-1 increase systemic and specific tissue protein incorporation and reduce protein catabolism, it would be expected that the combination would be likely to have similar, even possibly additive, effects. However, in cancerous states, rapid protein buildup and a decrease in turnover could potentially have deleterious effects since it would be expected that the tumor would preferentially increase its protein build-up and, accordingly, its mass. Therefore, making such a combined treatment could be considered foolhardy. However, the experimentation which lead to the present invention was directed to test this hypothesis.

Accordingly, an object of the invention is to provide a method of treating cancer with a combination- of total parenteral nutrition and parenteral administration of IGF-1.

Another object of the invention is to provide a total parenteral nutrition diet with additives including other factors along with the IGF-1 that slow or may even reverse tumor growth.

A further object of the invention is to provide a total parenteral nutrition diet which has beneficial effects for organ and total body protein without increasing protein production in a sarcoma or carcinoma and the attendant deleterious affects. These and ^"other objects and features of the invention will be apparent from the following description and the claims.

Summary of the Invention

The present invention features a combination therapy which is useful in the treatment of patients with cancer. This combination therapy is accomplished by parenteral administration of an effective amount of Insulin-Like Growth Factor-1 in combination with a.total parenteral nutrition diet. This total parenteral nutrition diet should include lipid sources, protein sources, carbohydrate sources, and essential vitamins and minerals. Total parenteral nutrition diets are well-known and certain diets of this type may be purchased in prepackaged form, e.g., the diet under the tradename Nutrimix from Abbott Labs. United States Patent Application Serial No. 822,526, the disclosure of which is incorporated herein by reference, describes a preferred nutrition diet. The total parenteral nutrition diet may also include additional non-essential nutrient components which have been shown to foster protein metabolism including glutamine and its congeners, arginine, nucleotides, nucleosides, and short-chain and medium-chain fatty acids and triglycerides. The Insulin-Like Growth Factor-1 can be either in native, preferably purified form or recombinant IGF-1 may be used. This combination treatment has applicability to a broad variety of cancers, with sarcomas, carcinomas and carcinosarcomas being particularly adapted to this type of treatment. The fat or lipid content of the total parenteral nutrition diet may be modified, as desired, to provide certain other beneficial effects. For example, a structured lipid may be used. One structured lipid which is particularly advantageous has at least one medium-chain fatty acid residue and at least one ω-3 fatty acid residue on the same structured lipid. This type of structured lipid, which is described in United States Patents Nos. 4,906,664, 4,871,768 and 5,081,105, the disclosures of which are all incorporated herein by reference, has itself shown anticancer properties as well as beneficial effects in treating cancer cachexia states. Other lipids which may be useful in the total parenteral nutrition diet include ω-3 fatty acids, particularly C18-C22 «^-3 fatty acids, monounsaturated fatty acids such as oleic acid, and ω-9 fatty acids. In any diet, there should be sufficient ω-6 fatty acids, particularly linoleic acid, as they are necessary for essential nutrition. By limiting the amount of linoleic acid using other lipid sources, certain beneficial side effects may be found. However, the beneficial effects of the present invention are evident, as is shown by the examples herein, even when using a classic TPN solution with its attendant high ω-6 fatty acid content.

The Insulin-Like Growth Factor-1 can be added as part of the total parenteral nutrition diet or may be given parenterally separately. A range of 5-50 μg/kg/hr IGF-1 is particularly advantageous for treatment of cancer. The advantages of the methods of the present invention will be more clearly set forth with reference to the following description.

Detailed Description of the Invention

The present invention provides a method of treating the cancer patient to promote protein metabolism and overall wellness without increasing tumor growth rate in a commensurate manner. The beneficial effect is accomplished by a combination therapy whereby Insulin-Like Growth Factor-1 (IGF-1) is given parenterally in conjunction with a total parenteral nutrition diet. The surprising result of this combination therapy is slowed tumor growth while providing overall better protein kinetics.

The following examples will more clearly illustrate the efficacy of the invention.

Example 1

In this example, normal male Sprague-Dawley rats were either fasted or fed a total parenteral nutrition (TPN) diet. Each group of rats then received either IGF-1 or saline. A silastic catheter was inserted through the internal jugular vein in all the rats and the rats received either saline solution (fasted group) or the TPN solution. Continuous infusion of ¹⁴C-leucine was used to analyze protein kinetics. Table 1 shows the ingredients of the TPN diet. TABLE 1

0.5 ml of MVC 9 + 3 vitamins and 0.25 ml of choline chloride (30% w/v) were added per 100 ml of hyperal solution .

Table 2 shows plasma leucine, total energy expenditure (TEE), respiratory quotient (RQ) , insulin levels, and glucose levels for the four groups (the fast and fed rats receiving IGF-1 or saline).

TABLE 2

Group Plasma TEE RQ Insulin Glucose Leucine (u ol/ml) (Kcal/ (mg/lOOml) kq/flgy) fasted, .137+0.008 123±3 0.89±0.01 13.9±1.3 76±2 IGF fasted, .126±0.004 119+6 0.89±0.01 15.5+.0 87+4 saline fed, .139±0.008 113±11 1.16+0.02 57.5±8.3 148±3 IGF fed, .153±0.006 142+4 1.16+0.03 51.6+4.5 155±7 saline The combination of IGF-1 and total parenteral nutrition abolishes the normal increments in energy expenditure (TEE) seen in TPN feeding alone. In addition, there is substantially no increase in plasma leucine from the combination of IGF-1 and TPN as compared with TPN alone.

Table 3 shows the whole body leucine kinetics in terms of percent flux oxidation, leucine flux, oxidation (Oxid), protein synthesis (Syn), protein breakdown (Brk), and leucine balance.

TABLE 3

WHOLE BODY LEUCINE KINETICS

Group Flux Ox Flux Oxidation Syn Brk Leucine

Balance

-umol/100g/h-

fasted 26.0+0.6 33.3+1.8 8.7+0.6 24.6+1.4 33.3+1.8 -8.7+0.6 IGF fasted 26.4+1.6 26.6+2.4 7.1+0.7 20.0+1.9 27.1+2.4 -7.1+0.7 saline fed 26.1+3.4 44.8+3.5 11.6+.1.7 33.2+3.1 17.5+2.9 15.7+1.7 IGF fed 35.1+1.2 40.8±1.7 14.3+0.8 26.4+1.2 12.9+1.4 13.5±0.5 saline

The combined diet abolishes the increment in percent flux oxidation from fasted to fed state, promoted the highest level of protein synthesis, and increased the leucine balance. This leucine balance increase is not as great as might be, however, because that the protein breakdown rate is higher for the combination therapy than it is for TPN alone.

Table 4 shows the muscle parameters, comparing the fasted and fed states, with and without the IGF-1, in terms of percent protein, fractional synthetic rate (FSR), protein synthetic rate (PSR) , intercellular specific activity vs. plasma specific activity of leucine (S£/Sp) and protein breakdown. FSR is the percentage of a tissue sythesized/day while PSR is the total protein synthetic rate of that tissue.

TABLE 4

MUSCLE PARAMETERS

^protein FSR PSR Si/Sp Brk μmol/g/h ^•μmol/g/h

fasted 12.7±0.7 2.5+0.5 2.18+0.30 0.83+0.10 0.056+0.22 IGF fasted 13.7+0.5 2.4+0.2 2.49+0.46 0.65+0.06 0.134+0.58 saline fed 13.5+0.5 4.4+0.9 3.54+0.65 1.26+0.21 -0.007+0.041 IGF fed 13.2±0.5 5.0+0.5 4.10+0.38 0.92+0.04 0.026+0.012 saline

The results of Table 4 are particularly surprising in terms of the ratios of specific activities and the muscle protein breakdown. The specific activity ratio for the combination therapy suggests reduced muscle breakdown, a finding heretofore never suggested. This is confirmed by he negative protein breakdown figure, showing that even for the normal rats, the combined therapy has particular effectiveness in protein sparing.

These results demonstrate that the combination of IGF-1 and total parenteral nutrition diet provides substantial benefits for any malnutrition state, not just cancer.

Example 2

In this example, tumor-bearing rats were dosed parenterally with saline, IGF-1 alone, TPN alone, or a combination of IGF-1 and TPN. The combination therapy provided substantial benefits to these tumor bearing rats.

Male Sprague-Dawley rats were inoculated with Walker 256 carcinosarcoma. Six days later, silastic catheters were surgically canulated into the internal jugular vein. Commencing on day 8, the rats received intravenous infusion of recombinant human IGF-1 (20 μg/kg/h-Genentech, Inc.) alone for 5 hours, TPN alone for 24 hours, saline, or the combination therapy of TPN alone for 24 hours and IGF-1 for the last 5 hours. The TPN solution was the same as described in Example 1, with a standard safflower and soybean oil lipid component. Continuous infusion of ¹⁴C-leucine was used to analyze protein kinetics.

Table 5 shows the whole body kinetics in terms of leucine flux, protein breakdown (Brk), percentage flux oxidation, leucine oxidation, protein synthesis, resting energy expenditure (REE), and respiratory quotient. TABLE 5

WHOLE BODY LEUCINE KINETICS IGF-1+TPN TPN IGF-1 Saline

128.36+4.29 86.61.+4.54 84.04+5.91

60.60+4.15 86.61+4.54 84.04+5.91

30.4+2.7 23.8+1.3 23.0+1.4

38.64+2.99 22.29+2.93 20.02+2.31

90.41+6.99 69.50+5.09 66.51+5.97

152.00+9.76 139.37+5.22 140.93+5.5

1.146+0.015 0.863+0.013 0.837+0.012

While there are significant differences in values between the rats which received TPN (either alone or in combination with IGF-1) and those who did not receive TPN, the only clinically significant result of Table 5 is in terms of resting energy expenditure. The addition of the IGF-1 to the TPN solution reduced the resting energy expenditure instead of the expected increased caused by added nutrition. This result is important in that it signifies the maintenance of host energy expenditure by diet modification.

Table 6 shows muscle breakdown (Brk) and the fraction of protein massed renewed per day (K_s) for each of the test groups

TABLE 6

MUSCLE PARAMETERS

IGF-1+TPN TPN IGF-1 Saline

Brk .-0.026+0.017 0.028±0.025 0.073+0.014 0.068+0.014 (μmol/h/g)

K_s(%/d) 4.6+0.4 4.8+0.5 3.1+0.2 3.3+0.3

The most significant result is that the combination of IGF-1 and TPN causes a reversal in muscle breakdown while neither TPN nor IGF-1 alone caused such a reversal. This sparing of muscle by using the combination therapy is particularly important in cachetic patients. Table 7 concerns the protein kinetics for the tumor itself. This table shows protein breakdown (Brk), fractional protein mass renewed per day (K_s), protein synthesis (Syn) , and the tumor protein synthesis rate minus the tumor protein breakdown rate (T_β-Tb) •

TABLE 7

TUMOR PARAMETERS

IGF-1+TPN TPN IGF-1 Saline

Brk 0.437+0.058 0.468+0.100 0.376+0.057 0.457+0.074 (μmol/h/g)

K_s(%/d) 33.5+2.3 41.2+.3.4 40.6+5.1 30.5+2.8

Syn 0.947+0.082 1.221+0.094 1.148+0.151 0.780+0.073 (μmol/h/g)

^~ _S-^~b 0.510+0.113 0.753+.0.136 0.772+0.122 0.323+0.043

The results shown on Table 7 are striking. Although either TPN or IGF-1 alone causes an increase in K_s, the combination therapy does not. Similarly, both IGF-1 and TPN alone cause increases in tumor protein synthetic rate, showing that the tumor mass was being increased by the treatment, while the combination therapy provided a substantially lower change in synthetic rate. The net tumor protein increase (T_S-T_D) was also significantly less for the combination therapy then the TPN or IGF-1 treatments alone. These results indicate that the combination of IGF-1 with TPN can attenuate muscle protein breakdown and maintain host energy expenditure without stimulating tumor protein synthesis. This unexpected result allows treating the cachexia and other energy expenditure problems of the cancerous state without the attendant problem of aggravating the tumor growth rate.

Those skilled in the art may determine other methods and materials which provide the advantages of the present invention. Such other methods and materials are intended to be included within the following claims.

What is claimed is:

Claims

1. A method of treating cancer in a patient through the use of nutritional support therapy comprising the step of parenteral administration of an effective amount of insulin-like growth factor-1 in combination with a total parenteral nutrition diet.

2. The method of claim 1 wherein said insulin-like growth factor-1 comprises recombinant insulin-like growth factor-1.

3. The method of claim 1 wherein said cancer comprises a sarcoma.

4. The method of claim 1 wherein said cancer comprises a carcinoma.

5. The method of claim 3 wherein sarcoma comprises a carcinosarcoma.

6. The method of claim 1 wherein said total parenteral nutrition diet comprises a structured lipid.

7. The method of claim 6 wherein said structured lipid comprises a lipid having a medium-chain fatty acid residue and an ω-3-fatty acid residue on the same structured lipid.

8. The method of claim 1 wherein said total parenteral nutrition diet comprises ω-3-fatty acids.

9. The method of claim 1 wherein said total parenteral nutrition diet comprises monounsaturated fatty acids.

10. The method of claim 9 wherein said monounsaturated fatty acids comprise oleic acid.

11. The method of claim 1 wherein said insulin-like growth factor-1 is added to said total parenteral nutrition diet in a range of 5-50 μg/kg/hr.

12. A total parenteral nutrition diet for treatment of cancer comprising nutritionally effective amounts of protein carbohydrate, lipid, and essential vitamins and minerals in conjunction with an effective amount of IGF-1.

13. The diet of claim 12 further comprising glutamine and its congeners.

14. The diet of claim 12 further comprising arginine.

15. The diet of claim 12 further comprising nucleotides or nucleosides.

16. The diet of claim 12 wherein said lipid comprises a structured lipid.

17. The diet of claim 16 wherein said structured lipid comprises a medium chain fatty acid residue and an ω-3 fatty acid residue on the same backbone.

18. The diet of claim 12 wherein said lipid comprises short chain fatty acids.

19. The diet of claim 18 wherein said short chain fatty acids are in the form of residues or a structured lipid.