Life Extension Magazine®

Protocols

New studies appear regularly on the treatment of cancer. Here is the Foundation's overview on molecular oncology, and treatments.

Scientifically reviewed by: Dr. Gary Gonzalez, MD, in October 2024. Written by: Life Extension Editorial Staff.

PROTOCOLS

Molecular Oncology

New scientific studies appear regularly on the treatment of cancer. Here, the Foundation publishes an overview on molecular oncology- the study of tumors-and treatments.

The following information is extremely technical. The cooperation of an oncologist is vital to cancer patients who seek to use this information in an attempt tosave their lives.

The family of RAS proteins plays a central role in the regulation of cell growth and integration of regulatory signals that govern the cell cycle and proliferation. Mutant RAS genes were among the first described "oncogenes," capable of transforming cells into cancerous phenotypes. Mutations in one of these three genes (H, N and K-RAS) encoding RAS proteins have been shown to be intimately associated with unregulated cell proliferation, and are found in an estimated 30 percent of all human cancers. The frequency of RAS mutations appears to depend upon the specific tumor type analyzed. For example, 90 percent of pancreatic carcinomas contain a mutated oncogenic RAS protein, while RAS mutations are rarely found in breast carcinomas.

Approximately one-third of liver cancers harbor a mutated RAS oncogene. The drug pravastatin (Pravachol), an inhibitor of the rate-limiting enzyme of cholesterol synthesis, inhibits the growth of liver cancer cells. One of the possible mechanisms of pravastatin's inhibition of cell growth is that pravastatin may inhibit the activity of RAS proteins. In a recently published study, patients with primary liver cancer were treated either with the chemotherapeutic drug 5-FU or a combination of 5-FU and 40 mg per day of pravastatin. Median survival was 26 months in the combination therapy group, versus 10 months in the monotherapy (5-FU only) group.

The highest incidences of RAS mutations are found in adenocarcinomas of the pancreas (90 percent), the colon (50 percent), the lung (50 percent), thyroid tumors (50 percent), liver tumors (30 percent), and myeloid leukemia (30 percent). If you have one of these cancers, you should consider requesting an immuno-histochemistry for the mutated RAS oncogene or a biopsied specimen in order to ascertain if the combination of chemotherapy and a statin drug may be effective.

Determining p53 status

Another of the most widely studied molecular changes in epithelial malignancies is mutation of the p53 tumor suppressor gene, which has been found in approximately 50 percent of solid tumors. The p53 gene product is regarded as a cell-cycle checkpoint, arresting progression through the G phase of the mitotic cycle (cell division) in response to cellular injury and allowing time for repair of replication errors. Mutant p53 allows tumor cells to bypass the cell-cycle constraints that facilitate repair or promote apoptosis (programmed cancer cell death).

P53 dysfunction promotes the spontaneous emergence of mutant cells and encourages the progression of cancer. Mutant p53 might inhibit the benefits of therapy since many cancer drugs and radiotherapy operate via the induction of DNA damage and p53-dependent apoptosis. Clinically, the presence of p53 mutations is indeed associated with intransigence to treatment, and both in vitro and in vivo studies with human cell lines and transplantable tumors have demonstrated enhanced survival of p53 mutant or null cells in the face of normally lethal concentrations of cytotoxic drugs and ionizing radiation.

A determination of p53 status by an immuno-histochemistry can help determine whether genotoxic chemotherapy and/or radiotherapy are likely to work, and can even help determine whether natural therapies such as soy genistein will be effective. In a recently published study, genistein was shown to inhibit growth and induce differentiation in human melanoma cells in vitro. The effects of genistein were regulated by cellular p53. Functional p53-containing cells were not suppressed by genistein. However, mutant p53-containing cells were significantly more sensitive to genistein's inhibitory and cell-differentiating effects.

The following laboratory can perform immuno-histochemistries to determine RAS and p53 status: IMPATH Laboratories 1010 Third Avenue, Suite 203 New York, NY 10021 Phone: 1-800-447-5816

Determining thrombotic risk factors

In patients affected with different tumors, disorders of blood clotting are frequently observed. The biological processes leading to coagulation are probably involved in the mechanisms of metastasis, the spread of tumors to sites throughout the body. About 50 percent of all cancer patients, and up to 95 percent of those with metastatic disease, show some abnormalities-a pre-thrombotic state-in the coagulation-fibrinolytic (blood-clotting) system. Thromboembolic complications are seen in up to 11 percent of cancer patients, and hemorrhage occurs in about 10 percent. Thromboembolism and hemorrhage, as a whole, are the second most common cause of death after infection.

In a recently published study, subclinical changes in the coagulation-fibrinolytic system were frequently detected in lung cancer patients. Five conventional and one new test of blood coagulation-that is, platelet count (P), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (F) and D-dimer of fibrin (DD)-were prospectively recorded in a series of 286 patients with new primary lung cancer. A pre-thrombotic state (depicted by a prolongation of PT, PTT, and increase of D-dimer of fibrin, the essential portion of a blood clot) was significantly associated with an adverse outcome.

Anticoagulant treatment of cancer patients, particularly those with lung cancer, has been reported to improve survival. These interesting (though preliminary) results of controlled trials lend some support to the argument that activation of blood coagulation plays a role in the natural history of tumor growth.

Recently, two studies compared the effectiveness of standard heparin with low molecular weight heparin (LMWH) in the treatment of deep vein thrombosis (DVT). (Heparin, which occurs naturally in the body, can be administered as an anticoagulant agent.) In both studies, mortality rates were lower in the patients randomized to LMWH-that is, they were assigned to treatment groups according to a probability distribution to reduce the chance of extraneous factors influencing the outcome of the study. The analysis of these deaths reveals a striking difference in cancer-related mortality.

Cancer-related mortality of patients treated with standard heparin was 31 percent, versus only 11 percent among those treated with low molecular weight heparin. This difference cannot solely be attributed to thrombotic or bleeding events. Because large numbers of cancer patients were included in the studies, it seems unlikely that ones with more advanced tumors were present in the standard heparin group.

Although it is also possible (based on the above results) that standard heparin increases cancer mortality, such an adverse effect has not been reported. These considerations suggest that low molecular weight heparin might exert an inhibitory effect on tumor growth that is not apparent with standard heparin. The evidence of lowered cancer mortality in patients on LMWH has renewed interest in these agents as "antineoplastic" (halting malignant cells) drugs. If your oncologist will not test for thrombotic risk factors, contact the Life Extension Foundation at 1-800-544-4440.

Assessing immune function

In order to assess the effectiveness of immune-boosting therapies, a complete immune cell subset test could be performed bimonthly in order to measure CD4 (T-helper) total count, CD4/CD8 (T-helper to T-suppressor) ratio, and NK (natural killer cell) activity.

CD4 T-cells have been shown to differentiate into Th1 or Th2 cells, with different cytokine profiles and functions. Th1 cells produce interleukin-2 and interferon gamma, activate macrophages (a cell involved in immune function), and cause delayed-type hypersensitivity reactions, whereas Th2 cells produce interleukin-4, interleukin-5 and interleukin-10, cause eosinophilia, and are more specialized in providing B cell (antibody) help for immunoglobin production. The differential development of these immune-system subjects is a major determinant of the outcome of physiological as well as pathological immune responses to cancer.

One of the soluble factors secreted by monocytes, interleukin-12, is a major cause of differentiation of T cells towards the Th1 type, while suppressing Th2 cytokine development. The capacity of interleukin-12 to stimulate growth and interferon gamma production in T cells and NK cells is probably the main reason for its Th1-inducing capacity.

Another product of activated monocytes, prostaglandin E2 (PGE2), has been shown to be an important regulatory factor in inducing Th2 responses. PGE2 T-helper responses opposite to interleukin-12: the synthesis of Th1 cytokines (interleukin-2 and interferon gamma) is much more sensitive to inhibition by PGE2 than Th2 cytokine production (interleukin-4, interleukin-5, interleukin-10). Because Th1 and Th2 cytokines negatively cross-regulate each other's production, the selective inhibition of Th1 cytokines by PGE2 could result in dominant Th2 responses.

These findings provide opportunities to treat patients with dominant Th2 responses by selectively inhibiting synthesis of PGE2 during therapy, as this would increase interleukin-12 production and cause a shift toward Th1 cytokine production.

Many human tumors-including gastric, colon, estrogen receptor-negative breast, prostate and lung-produce more prostaglandin E2 than their associated normal tissues. The mechanisms and implications are not fully understood, but PGE2 may act as a tumor promoter in tumor angiogenesis (formation of tumor-feeding blood vessels), in cachexia (wasting syndrome) and in the suppression of immune function.

Prostaglandins are synthesized from arachidonic acid by the enzyme cyclooxygenase. There are two isoforms of cyclooxygenase: Cox-1 is expressed constitutively (in regular, fixed amounts) in most tissues and helps maintain gastric mucosal integrity; Cox-2 is inducible (stimulated by an inducing agent) and is associated with cellular growth and differentiation. In a recently published study, PGE2 was shown, for the first time, to increase the levels of its own synthesizing enzyme, Cox-2, in four human cells lines.

In this regard, it is conceivable that cells continuously sustain their growth in part by using extra cellular PGE2 that they themselves produce and release to increase the expressions of Cox-2 and possibly other growth related genes. Elevated Cox-2 expression may make cancer cells resistant to death by apoptosis. Thus, inhibition of excess activity with Cox-2 specific non-steroidal anti-inflammatory drugs (NSAIDS) might restore the cell's ability to die and so cause tumor regression.

Super aspirins that selectively inhibit Cox-2 are being developed by several drug companies to try to avoid the side effects of NSAIDS. The currently commercially available NSAIDS are nonselective Cox inhibitors and are associated with peptic ulceration in the stomach. Nimesulide is a novel NSAID that is 100 times more selective for Cox-2 than for Cox-1.

In a recently published study, patients received either nimesulide or aspirin for 14 days. PGE2 formation fell markedly in the nimesulide-treated patients, whereas aspirin had no effect. In contrast, nimesulide had no significant effect on thromboxane B2-a platelet-aggregating substance in the body that may lead to thrombosis-which was suppressed by aspirin. Nimesulide suppressed Cox-2 in vivo with no detectable effect on platelet Cox-1.

Nimesulide has been commercially available throughout most of the rest of the world for more than 10 years, but has not been licensed by the Food and Drug Administration for use in the United States. The Life Extension Foundation has identified sources that will ship nimesulide to Americans for personal use.