Govallo Placental Extracts Detailed Scientific Review

Overview

Background

In contrast to most immune therapies that seek to stimulate the immune system of the patient, the Govallo therapy seeks to weaken or suppress the factors within the tumor that "turn off" what would be normal immune responses of the patient. Similarities between tumors that have evaded immune defenses and the developing fetus that is protected from the maternal immune system led the Russian physician, Dr. Valentin I. Govallo, MD, PhD, to develop a treatment for cancer using placental tissues.

The placenta is an interface between fetal and maternal blood and lymphatic systems. It contains cells known as trophoblasts that play a major role in protecting the fetus from the maternal immune system. These factors are selective, however, in that the maternal immune system is selectively, and not generally, suppressed¹.

Theories that trophoblastic cells in the placenta might also play a role in the development of cancer were discussed in the early 1800s and tested in 1911 by inoculating embryonic tissues at all stages of development into a variety of adult animals. These theories were not supported by results, however, as the injected trophoblastic cells just grew for a time and then became mature cells that did not look like malignant cells². (Of course, some malignant cells may look like normal cells and only differ in the rates in which they divide.)

An extensive review of trophoblastic theories was completed in 1975 by Charles Gurchot³ who rejected the idea of wandering trophoblastic cells, but investigated other similarities with cancer cells. First, he noted the similar endocrine profiles produced by both trophoblastic and cancer cells: Human Chorionic Gonadotrophan, (HCG), Adrenocorticothrophic hormone (ACTH), Growth Hormone (GH) and Melanocyte Stimulating Hormone (MSH). (Carcinoembryonic antigen, Alpha feto protein, and oncomodulin have subsequently been discovered.) He also noted that the immunological properties of the two cell types were similar and that any cell could be induced to become malignant through radiation or chemicals. The basis for his expanded version of the trophoblastic theory was that "all cells have a fund of genetic information which they do not use or express", but damage to genetic suppressors from any cause, allows these suppressed asexual division mechanisms to become active³.

Valentin Govallo further developed the trophoblastic theory in the 1960s by associating the full reactivation of the mother’s immune system following pregnancy with placental factors that appeared to be turned on at birth. His in vitro and animal studies eventually led him to the actual treatment of cancer patients with placental extracts obtained from live full-term deliveries². His therapy, (Immunoembryotherapy or VG-1000)², is promoted by the Center for Empirical Medicine⁴ and used along with other treatments at the Immune Augmentative Therapy (IAT) clinic in Freeport, Bahamas, the Gerson Clinic in Tijuana, Mexico, and the San Diego Clinic in California^4,5. Different preparations of placental extracts (e.g. "Placentex") have been used in other clinics⁶.

Proposed Mechanism of Action

Govallo believed that the mother’s immune system acceptance of the fetus weakened in the latter part of pregnancy and disappeared at delivery. He theorized that the host-tumor interaction involved a similar "pregnancy like" suppression of the host immune system and that it could be counteracted by immunization with an extract from the placenta of a live, full-term delivery. Such a placenta would theoretically contain a high concentration of substances that would return the immune system to its normal state. He tested placental extracts in vitro and reported that they suppressed lymphocytes from maternal tissue (details provided in his book published in 1991)².

Related Research by Others

Some spontaneous abortions occurring early in pregnancy have been associated with maternal interactions with immune factors present on sperm¹.

Major histocompatibility (MHC) antigens, presented on the surfaces of both fetal and tumor cells, are limited to those that would be recognized as "self" by the mother/host^1,7,8. Oncogenes are known to exist in an inactive state maintained by suppressor genes that may be turned on later if the suppressor genes are damaged⁷.

Human chorionic gonadotropin (HCG) is one of the hormones produced by both the placenta and by common cancers^1,9. Purified extracts of this hormone derived from the urine of pregnant women have been tested in randomized clinical trials for patients with Kaposi’s sarcoma¹⁰. Variable outcomes of these trials have been attributed to immune responses to any foreign substance, possible contamination and/or the complexity of hormone and host interractions^10,11. Others have investigated the role of nitric oxide in maternal tolerance of the fetus¹², expression of an extracellular inducer of matrix metalloproteinase¹³ and antitumor properties of proteins isolated from the urine of pregnant women¹⁴.

These theories and investigations of fetal-cancer cell similarities have been complicated by several factors. One^10,14 is that immune responses to placental extracts may simply be non-specific responses to the introduction of any foreign substance. Another is that maternal suppression of immune response has not been found to generally decline toward the end of pregnancy although pregnant mice inoculated with Kaposi’s sarcoma are less likely to develop tumors if injected early in pregnancy¹⁴.

Toxicity

Fever, shivering and light weakness were observed in the series of patients treated by Govallo. Although these symptoms did not require any medication and disappeared in 24 hours, they indicate reactions to foreign proteins that could be serious. Placental extracts contain many bioactive molecules, some of which may actually stimulate the growth and division of malignant cells as demonstrated by one study of melanoma cells¹⁵ and the variable effects of the trials for Kaposi’s sarcoma^10,11,14.

Summary of Research

Amount and Type of Research

A search of the Medline database and other key databases (CINAHL, AltHealthWatch, SCOPUS) between 07/01/2005 and 05/15/2007 identified no new human studies.

Our previous reviews of the literature and other sources had identified 12 references to Govallo’s therapy, of which 12 (100%) were applicable to cancer.

Of the combined total of 15 articles, we retrieved 15 (100%) and classified the references into the following types of information:

*Note that one of these is the book by Govallo that contains a clinic series plus extensive discussion and references to in vitro and in vivo studies in animals concerning related aspects of immunity, pregnancy and cancer. However, his animal studies did not involve injecting of placental extract into animals with cancer and observing either regression of tumors or survival.

Of the human related articles, we coded the studies (2) by the following study designs:

*Unpublished set of case reports that was a subset of the case-control study.
*Numbers in parentheses indicate trials designed to evaluate the specific effects of Govallo Placental Extracts.

Summary of Human Research

Reviews of the literature have identified two human studies. One was a case control study of 35 patients with various sites of cancer who received placenta extract plus other unknown immune therapies after they had failed conventional therapy. The controls were 66 who only received the other immunotherapy, details of which were not described. Side effects of the therapy included fever, shivering and weakness. Although no statistical results were provided, those in the placenta group had much better three-, five- and 10-year survival (87%, 77% and 49%, respectively) compared to 12%, 6% and 2% in the control group².

An unpublished set of 35 case reports¹⁶ was received by the former University of Texas Center of Alternative/Complementary Medicine research. However, all but six of these cases had been previously summarized in the study described in the preceding paragraph². The second published study was a randomized clinical trial for 120 patients with radiation mucositis. Half received injections of a placental extract known as "placentrex" and the other half received conventional treatment consisting of "disprin" gargles and betamethasone oral drops. Fewer patients treated with the placentrex had progression to more severe mucositis and more of them had subjective improvement in swallowing, but no measures of statistical significance were provided⁶. Additional problems are that the "disprin" gargles are not described and the treatment of the controls is not known to be a standard of care.

This research in humans is also summarized in the Govallo Human Study Table and in the Annotated Bibliography.

Annotated Bibliography

¹Govallo, V. Immunology of pregnancy and cancer. Nova Science Publishers, Inc.; 1993.

Cases and case-control study reviewed below were included in Govallo’s book.

The following two cases (pages 203-210) appear to be a subset of the case control study described below.

Case #1 (Mrs. Sh.) - Large squamous cell carcinoma from mediastinum extending into lung - surgery removed - same day patient injected subcutaneously in thigh with 20 ml placental extract combined with 2 ml of freshly drawn venous blood. Within a month, the sizes of the metastatic shadows in the lung diminished considerably (x-rays pictured in book). Within three months, the foci practically not found; normal structure for lung tissue observed four and 7.5 years after surgery. Patient died in 1983 (unclear how many years later) from a heart attack. Autopsy revealed no traces of cancer.

Case #2 (Mr. Sh.) - (husband of above) Squamous cancer of lower lobe of the right lung with involved lymph nodes of the lung and mediastinum plus a chondroma of the middle lobe. Surgery removed - x-ray three weeks later revealed no pathological changes - immunization with placental extracts done at the same time. In four months, the absence of blocking factor in reactions to cancer antigen and PHA was recorded. One year later, infiltrate appeared in lung and a second immunization with placental extracts was done. At four and 15 years he had no physical complaints.

Case-control study (pages 210-217):

Purpose: Survival.
Type of Study: Case control
Methods: (Various) Thirty-five patients treated with placental extracts* had cancer of the breast (18 - including one male), lung (7), malignant hemangiopericytoma (10), synovial sarcoma (10) plus 10 patients each having a cancer of the cecum, ovaries, uterus, kidneys, bartholin's glands and submandibular salivary gland. (Note: The cancers for the last group of 10 patients do not add up to 10 and the total for all cancers does not add up to 35.) A control group of 66 patients treated with immunotherapy had a similar variety of cancer sites except that there were more osteosarcomas. Both groups had failed conventional treatment with surgery, radiotherapy and chemotherapy.

*Placental extracts from a number of placenta were tested (LAI test) to determine which extract provided the strongest blocking effects in a suspension of a patient's leukocytes, embryo antigen and medium. The extract which most strongly inhibited a reaction; that is acted as a serum with blocking effects upon cell response to embryo antigens, was injected into the patient. If an LAI test with embryo or tumor antigens and the reaction of blast transformation of lymphocytes with PHA still showed the presence of blocking activity in the patients blood serum, then repeated immunizations of placental extract were given. In addition to placental extracts, thymus extracts obtained from non-viable miscarried fetuses were injected beginning one week after the placental extract and continuing for two to four weeks.

Results: There was some fever, shivering and light weakness. In a few days, patients' conditions noticeably improved. Patients reported tactile sensations in the metastatic sites. The following table indicates the survival differences between this placental treatment group and the immunotherapy controls: *Corrected from original published percentage.

Survival Group	Three years No. (%)	Five years No. (%)	10 years or more No. (%)
Immunotherapy (n=66)	8 (12.1)	4 (6.0)	2 (3.0)
Immunoembryotherapy (n=35)	31 (88.6)	27 (77.1)	17 (48.6*)

*Corrected from original published percentage. No measures of statistical significance were provided.

Caution concerning this report: This report was not published in a peer-reviewed journal; that is, it was not reviewed by experts in the field to determine that there was sufficient data to support the conclusions.

⁶Kaushal V, Verma K, Manocha S, Hooda HS, Das BP. Clinical evaluation of human placental extract (placentrex) in radiation-induced oral mucositis. International Journal of Tissue Reactions 2001;23(3):105-10.

Purpose: Relief of side effects from radiation
Type of Study: Randomized, unblinded clinical trial
Methods: Patients (n=120) were enrolled in the study who had developed radiation mucositis after radiotherapy for head and neck cancers. Patients were excluded if they had early stage cancers, had only been treated with brachytherapy (internal radiation), only received palliative radiotherapy, had received previous radiotherapy or chemotherapy or had distant metastases. All eligible patients were treated on the same unit with the same size field. After developing radiation mucosistis, the patients were randomized to two groups of 60 each. One group received injections of Placentrex by deep intramuscular injection, five days a week for 15 injections. The other group received that clinic’s standard treatment consisting of disprin gargles and betamethasone oral drops. All patients were given topical antiseptic mouth washes (Betadine). Baseline radiation reactions were compared and graded according to the Radiation Therapy Oncology Group (RTOG) criteria. Patients were then monitored twice a week for progression of mucositis, pain control, infections, degree of difficulty in swallowing and need for a break in treatment.
Results: Demographic and disease characteristics were similar between the two groups. No side effects of treatment with Placentrex were mentioned. Higher percentages of patients treated with Placentex had decreases in pain and improvement in dysphagia, with less progression of mucositis to grade 3, less secondary infections and less needs for a break in treatment. These responses are illustrated in the following table adapted from table II of the article.

Observations	Placentex (n = 60)	Control (n = 60)
Decrease in pain	48/60 (80%)	22/60 (36.7%)
Progression of mucositis to grade 3	24/60 (40%)	52/60 (86.7%)
Improvement in dysphagia	56/60 (93.3%)	9/60 (15%)
Secondary infection	Nil	5/60 (8.3%)
Treatment break	1/60 (1.7%)	3/60 (5%)

Caution concerning this report: Although most of these results appear to show significant differences, no measures of statistical significance were provided by the authors and the lack of blinding in this study could have increased the risk of bias affecting these results.
Additional note: Disprin gargles, betamethasone and Betadine are not generally known to be standard care for radiation mucositis.

Reference List

1. Weetman AP. The immunology of pregnancy. Thyroid 1999 Jul;9(7):643-6.
2. Govallo VI. Immunology of Pregnancy and Cancer.Nova Science Publishers, Inc., 1993.
3. Gurchot C. The trophoblast theory of cancer (John Beard, 1957-1924) revisited. Oncology 1975;31:310-33.
4. Anonymous. Therapeutic cancer vaccine based on placental extracts. Alternative Medicine Digest 1997 Jan;(16):65-6.
5. Weiwel F. Personal communication.
6. Kaushal V, Verma K, Manocha S, Hooda HS, Das BP. Clinical evaluation of human placental extract (placentrex) in radiation-induced oral mucositis. International Journal of Tissue Reactions 2001;23(3):105-10.
7. Lewin B. Genes V. New York, NY: Oxford University Press; 1994.
8. Murphy SP, Choi JC, Holtz R. Regulation of major histocompatibility complex class II gene expression in trophoblast cells. Reproductive Biology and Endocrinology 2004;2:52-9.
9. Triozzi PL, Stevens VC. Human chorionic gonadotropin as a target for cancer vaccines. Oncology Reports 1999 Jan-1999 Feb;6(1):7-17.
10. Simonart T, Van Vooren JP, Meuris S. Treatment of Kaposi's sarcoma with human chorionic gonadotropin. Dermatology 2002;204(4):330-3.
11. Bisacchi D, Noonan DM, Carlone S, Albini A, Pfeffer U. Kaposi's sarcoma and human chorionic gonadotropin: mechanisms, noieties and mysteries. Biological Chemistry 2002 Sep;383(9):1315-20.
12. Gonzalez A, Lopez AS, Alegre E, Alcazar JL, Lopez-Moratalla N. Does nitric oxide play a role in maternal tolerance towards the foetus? J. Physiol. Biochem. 2004;60(3):227-38.
13. Li W, Alfaidy N, Challis J. Expression of extracellular matrix metalloproteinase inducer in human placenta and fetal membranes at term labor. The Journal of Endocrinology and Metabolism 2004;89(6):2897-904.
14. Pati S, Lee Y, Samaniego F. Urinary proteins with pro-apoptotic and antitumor activity. Apoptosis 2000 Feb;5(1):21-8.
15. Mallick S, Mandal SK, Bhadra R. Human placental lipid induces mitogenesis and melanogenesis in B16F10 melanoma cells. Journal of Biosciences 2002 Jun;27(3):243-9.
16. Govallo VI. Thirty-five cases. Unpublished Compilation received by the former University of Texas Center for Complementary and Alternative Medicine in 1997. Many cases are the same as those reported in².