Hydrazine Sulfate: A Current Perspective
[Nutrition and Cancer 9:59-66, 1987]
Hydrazine sulfate is an anticachexia agent which interrupts host energy wasting as a result of the malignant process. An inhibitor of gluconeogenesis at the phosphoenolpyruvate carboxykinase (PEP CK) reaction, this agent has been shown in randomized, placebo-controlled, double-blind trials to improve glucose tolerance, reduce glucose turnover, increase caloric intake, and increase or stabilize weight; in single-arm controlled trials, this agent has been shown to increase appetite, improve performance status, decrease pain, diminish anorexia, normalize laboratory indices, stabilize tumor growth, induce tumor regression, and promote survival, while inducing little to no important clinical side effects. In view of its demonstrated capacity to effect anticancer response, this drug is suggested for trial as a sole agent in early drug-resistant cancer, in combination with cytotoxic and related therapies, and in conjunction with total parenteral nutrition. It is postulated that effective control of the mechanisms associated with cancer cachexia may contribute to control of malignant disease.
Recent double-blind findings (1) indicate that hydrazine sulfate is capable of inducing statistically significant weight gain, as a function of caloric intake in late-stage cancer patients, in comparison to a similar group of patients treated with placebo. These findings reinforce earlier double-blind studies (2), in which it was established that this unique agent was capable of interrupting aberrant glucose recycling and turnover, presumed to be a primary mechanism of cancer cachexia (3-6), in patients with late-stage disseminated malignant disease. In an effort to better assess the clinical significance of these and related (7) findings, it is of value first to review the background and rationale of this agent.
Hydrazine sulfate acts to interrupt host energy-wasting effected as a result of a systemic interplay between tumor glycolysis and host gluconeogenesis (Figure 1). In this mechanism, first proposed in 1968 (8), lactic acid from the glycolyzing neoplastic tissue, amino acids from peripheral protein breakdown and glycerol from lipid mobilization, contribute to the development of a massive gluconeogenic pathway, in which progressively greater amounts of energy are lost from normal host sources in the obligatory conversion of these precursors to glucose. A point is reached in which host energy loss via gluconeogenesis exceeds dietary energy intake (via diminished appetite), with the consequent, and abrupt, onset of weight loss. It was therefore postulated that gluconeogenesis was the immediate thermodynamic mechanism for cancer cachexia and that inhibition of gluconeogenesis could result not only in an attenuation or reversal of cancer cachexia but also, in view of the systemic interrelationship between tumor energy gain and host energy loss, in possible inhibition of tumor growth as well (2).
Gluconeogenesis and glycolysis have been shown to be opposite types of pathways, sharing many of the same enzyme systems (Figure 2); however, in the interconversion of phosphoenolpyruvate (PEP) to pyruvate these pathways diverge, so that it becomes possible to impose a selective block against gluconeogenesis -a block which would have no effect on glycolysis and on the many vital normal tissues, such as brain, red blood cells and skeletal muscles, which derive a significant portion of their energy supply from this process. Thus gluconeogenesis could be blocked either at pyruvate carboxylase, catalyzing the conversion of pyruvate to oxalacetate or at phosphoenolpyruvate carboxykinase (PEP CK), catalyzing the conversion of oxalacetate to PEP without at all inhibiting the glycolytic enzyme, pyruvate kinase, which catalyzes the conversion of PEP to pyruvate. Because all precursors, with the exception of glycerol, enter the gluconeogenic pathway at the level of oxalacetate, inhibition of the enzyme PEP CK suggests itself as the most expedient means of inhibiting host energy-wasting and, indirectly, tumor growth, attendant on uncontrolled gluconeogenesis.
In 1969 and 1970 it was reported that hydrazine sulfate noncompetitively inhibited the conversion of oxalacetate to PEP. An inhibitor of in vivo and in vitro gluconeogenesis, this agent was indicated by metabolic cross-over studies to act specifically and irreversibly at the PEP CK reaction (9,10); it was therefore suggested as a feasible therapeutic measure for the inhibition of cancer cachexia and cachexia-dependent tumor progression.
Preclinical studies with transplantable animal tumors indicated hydrazine sulfate to produce antitumor effects, based on its anticachexia potential. These studies, initiated with the expectation that tumor inhibition would constitute a most sensitive indicator of cachexia inhibition -- in view of the thermodynamic interrelationship between the two -- also demonstrated the ability of hydrazine sulfate to potentiate and/or synergize the effect of other anticancer agents. Specifically, hydrazine sulfate was shown to inhibit the in vivo growth of such rodent tumors -- as Walker 256 carcinosarcoma, B-16 melanoma, Murphy-Sturm lymphosarcoma, L-1210 solid leukemia, S-180, Pliss lymphosarcoma, thyroid tumor and Morris hepatoma (11-15). This agent was likewise demonstrated to potentiate the antitumor action of cyclophosphamide (Cytoxan), mitomycin-C, methotrexate, bleomycin, 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), 5-fluorouracil (5-FU) and neocarcinostatin in various rodent tumors (16,17); synergism was reported with the cytostatic agent thiophosphoramide (Thiotepa) in Seidel hepatoma, Pliss lymphosarcoma and S-180 (18). These effects were indicated to be indirect (14) and not the product of direct drug action on proliferating cancer cells (2,19). Preclinical observations thus implicated cachexia inhibition at PEP CK to be causally linked to tumor inhibition (2,20,21) and such tumor inhibition to be indirect, not based on cytotoxicity and host-mediated.
Early clinical trials with hydrazine sulfate yielded mixed results. Nonrandomized and largely uncontrolled (with the exception of the newly initiated, single-arm Soviet trials), these studies demonstrated a preponderance of positive over negative findings. On the positive side, and consistent with the indicated mechanism of drug action, hydrazine sulfate yielded up to 70% anticachexia and 41% antitumor response, in long-term studies involving as many as 84 and 95 evaluable patients, respectively (22-26). Anticachexia findings included: increased appetite with weight gain or cessation of weight loss, increased strength and performance status, decrease in (or complete elimination of) pain, reduction of fever, normalization of the laboratory indices, reduction or disappearance of hemoptysis, diminished respiratory deficiency, and disappearance or reduction of severe weakness characteristic of the pretreatment period. Antitumor response consisted of tumor regression and tumor stabilization. It was stressed that these results occurred in patients who were "factually terminal" and who had become refractory to all other (previously successful) modalities of cancer therapy. In contradistinction, negative results were reported in short-term studies of 25, 25 and 29 patients, respectively (27-29). Two of these studies, which were deficient (18,30-32) in protocol design or implementation, nevertheless reported "transient" improvements, such as increased appetite with and without weight gain, decrease in bone pain, decrease in rate of reaccumulation of ascites following paracentesis, increased lung aeration and tumor regression. Side effects were reported to be mild and "transient" in nature, were limited to low incidences (generally under 5%) of nausea, pruritis, dizziness, drowsiness, excitation, "polyneuritis" (peripheral neuritis) and "euphoria" (mood improvement), appearing "only after a sufficiently prolonged course of treatment" and "differing materially from the toxic effects of cytostatics" (22,25,28,33). None of the following occurred: myeiodepression, leucopenia, thrombocytopenia, hypotension, organ toxicity, carcinogenicity or drug deaths. Although "major neurological toxicity" was cited in one study (29), in those studies in which there were no exceptions to protocol (23-27,33) there was no incidence of serious neurological or other disturbances.
Single-Arm, Soviet Trials
Although non-randomized or blinded, the large-scale, sole-agent Soviet trials, which comprised 356 evaluable patients and were carried out at the Petrov Research Institute of Oncology in Leningrad (7,34,35), acted to further define the results of earlier trials. Begun in 1975 and 1976 and referenced above (24,25) in its initial phases, this single-arm study differed from other uncontrolled trials in its strict exclusion of extraneous factors, such as concurrent or incompatible chemotherapy or medication or departures from accepted criteria of patient selection, dosage and evaluation. In this study, a) no concurrent medication other than "cardiotonics" or analgesics, if needed, was administered; b) patients with "prior therapy" (i.e., those treated within the previous 6 weeks) were excluded; c) study entry was restricted to late-stage patients for whom all other possibilities of therapy (e.g., surgery, radiotherapy, or other forms of therapy) had been exhausted; d) drug administration was limited to one 60-mg capsule or tablet of hydrazine sulfate per os for the first three days, 60 mg twice a day for the next three days, and up to 60 mg three times daily beginning on Day 7 (the equivalent of a 4% solution was administered in those patients with dysphagia); e) the length of a single course of therapy varied from four to six weeks, and in some instances, up to six months; f) repeated therapeutic courses (from 2 to more than 24) were separated by drug-free intervals of from two to four weeks; g) total length of treatment was up to seven years; and h) evaluation was carried out not earlier than six weeks following cessation of therapy and was based on direct clinical and laboratory measurements, histological data, and roentgenological and endoscopic examinations. Results of this nine-year study revealed the following: 50% subjective (anticachexia) response; 46% antitumor response; restoration of (previously lost) sensitivity to cytotoxics; instances of long-term survival; and the absence of important clinical side effects. Anticachexia effect was manifest in increased appetite and weight response, improved strength and performance status, and a reduction in paraneoplastic findings, as described previously, and was maintained for not less than 1.5 months. Antitumor response was manifest in 31% stabilized condition (111:356 patients) and an additional 15% tumor regression (52:356 patients) (tumor regression varied from less than 25% to greater than 50% of size of original primary lesion and/or metastases) also maintained for not less than 1.5 months. Therapeutic effects were indicated as frequently not appearing until the second or third course of therapy, and their accrual in patients who were "practically in the terminal phase" of their disease was cited as a "factor" of potential clinical significance.
Controlled Clinical Trials
Controlled clinical trials acted to clarify the mechanism of action of hydrazine sulfate and lend support to the Soviet results. The first of these, a prospectively randomized, double-blind, placebo-controlled study performed at Harbor-UCLA Medical Center in California (2,36), sought to examine the effect of hydrazine sulfate on aberrant carbohydrate metabolism in patients with cancer cachexia. The two treatment groups (placebo- and hydrazine sulfate-treated patients) were matched in terms of age, sex, performance status, prior and concurrent therapy, body weight, prior weight loss (16% of preillness weight in the placebo group vs. 19% in the hydrazine sulfate group), and other parameters. Initial in-patient metabolic evaluation in a total of 38 patients was followed by a 30-day per os treatment of capsules of either placebo or hydrazine sulfate in an escalating dosage of 60 mg, three times/day reached on Day 8, followed again by a similar period of in-patient evaluation. Results demonstrated statistically significant improvement in both oral glucose tolerance and rate of glucose production in patients receiving hydrazine sulfate compared with patients receiving placebo (p < 0.05), also that such improvement was not the result of changes in blood levels of insulin, glucagon or cortisol. Improved glucose tolerance in the hydrazine sulfate-treated patients was further related to weight stabilization or improvement: 78% of patients with improved glucose tolerance either improved or stabilized their weight, whereas all patients without improvement in glucose tolerance lost weight. Side effects were unremarkable: hypoglycemia was not seen, two patients experienced transient dizziness, and one patient from each arm of the study (placebo and hydrazine sulfate) experienced extreme nausea. It was concluded that hydrazine sulfate treatment significantly improves abnormal glucose metabolism associated with weight loss in patients with cancer.
In a second double-blind, placebo-controlled study, which was also conducted at Harbor-UCLA Medical Center (1), the effect of hydrazine sulfate on dietary parameters was determined in 58 evaluable, late-stage patients. Pretreatment clinical and nutritional parameters were similar in the placebo and hydrazine sulfate groups; tumor types studied consisted predominantly of non-small cell lung (35 patients) but also included colon (9 patients), ovarian (5 patients) and others. Pretreatment weight loss averaged over 29 pounds in 82% of the patients. After 30 days of treatment (in an escalating per os dosage of 60 mg, three times/day, reached on Day 8), it was shown that 78% of patients receiving hydrazine sulfate maintained or increased their weight, in comparison with only 38% of the patients receiving placebo (p < 0.05); caloric intake increased in 73% of the hydrazine sulfate patients compared with 59% of the placebo patients; increased caloric intake was associated with weight gain in 80% of all hydrazine sulfate-treated patients and with weight gain in 94% of the lung cancer patients receiving hydrazine sulfate, in comparison with only 50% of the lung cancer patients receiving placebo (p < 0.05). All dietary changes were independent of initial nutritional status. It was concluded that hydrazine sulfate administration increases the efficacy of ingested caloric intake and results in maintenance of body weight in patients with cancer.
The double-blind studies of Harbor-UCLA Medical Center clearly demonstrate that hydrazine sulfate brings about anticachexia response in terms of weight maintenance and stabilization. Even in the earlier, single-arm studies conducted in the United States and Soviet Union (7,37), which yielded results quantitatively and qualitatively different from those to be expected from placebo response or historical controls (38), this effect is manifest -most predominantly in weight gain and improved subjective response dependent on weight maintenance. The mechanism of this response appears to be that of previously described concepts (3,8,39), namely, a reversal of host energy-wasting attendant on uncontrolled gluconeogenesis, resulting in improved glucose tolerance, decreased glucose turnover (production), weight stabilization, increased caloric intake and statistical association of increased caloric intake with weight gain.
The mechanism of antitumor effect of hydrazine sulfate elicited to date in nonrandomized human trials and in preclinical animal studies (tumor stabilization and regression) is not so clear. Presumably these effects are indirect, resulting from an abridgement of tumor progression secondary to interruption of the systemic cycle of tumor energy gain-host energy loss. Such indirect effect is supported by in vitro and in vivo studies (3,19) demonstrating a lack of cytotoxic effect and by the large amounts of tumor stabilization and regression (7,35), uncharacteristic of cytotoxic response in late-stage patients. In contradistinction, recent evidence has shown a direct effect of hydrazine sulfate on certain tumors in tissue culture. Of three human glioblastomas, hydrazine sulfate was directly cytotoxic to one and resulted in cytotoxicity when added to a noncytotoxic concentration of BCNU in another (40). These data indicate that more than one mechanism of antitumor effect may exist and suggest the need for further studies to clarify this possibility.
Nonrandomized and randomized metabolic trials thus indicate hydrazine sulfate as a new anticachexia agent capable of indirectly, and perhaps to an extent directly, inducing a broad spectrum of antitumor responses in the absence of important clinical side effects. Clearly different from the action of cytotoxic agents, this new agent brings into focus the question of relationship between tumor progression and body wasting and the design of realistic therapeutic goals in the management and control of malignant disease.
Cancer cachexia is the most devastating aspect of the malignant process, accounting in large measure for a significant proportion of cancer morbidity and mortality (41,42). Any measure which can reverse this syndrome, holds the potential not only for significantly reducing cancer morbidity and extending survival time but also -insofar as tumor progression and cancer cachexia are functionally interrelated -effecting remission. Hydrazine sulfate has been identified by appropriately designed double-blind and single-arm studies to be a specific anticachexia agent, capable of inducing a wide range of therapeutic effects in late-stage patients. The outlook for this agent is thus promising, especially in regard to three distinct categories of potential drug use: hydrazine sulfate a) as a sole agent, b) in combination with cytotoxic chemotherapy and/or radiotherapy, and c) in combination with total parenteral nutrition (TPN).
Hydrazine Sulfate and TPN
In randomized trials TPN, via parenteral (and enteral) hyperalimentation, has in general failed to differentially replenish weight loss, improve survival or favorably influence the outcome of chemotherapy in patients with cancer, and in some studies infusion of calories into the malnourished cancer patient has been associated with decreased survival and other undesirable consequences (43-46). This lack of restorative effect is not surprising, because hyperalimentation per se fails to address the basic metabolic mechanisms underlying weight loss and cachexia and may itself contribute to tumor growth. In the former instance, for example, infusions high in glucogenic amino acids may bring about paradoxial effects; for these amino acids can be deaminated in the liver and kidney cortex, costing the body significant energy loss in their recycling to glucose and thus result in a catabolic, rather than anabolic, effect on the host (33). Without some means to suppress gluconeogenesis, cancer patients may continue to lose weight and remain in negative nitrogen balance. In combination with hydrazine sulfate, however, the outlook for hyperalimentation may improve significantly. For with a gluconeogenic blocking agent in place, TPN may be expected to restore positive nitrogen balance [as has been demonstrated experimentally in tumor bearing animals (19)], induce weight gain, improve performance status and enhance the ability to withstand chemotherapy.
Recent reports have identified hydrazine sulfate as a potential agent for use in acquired immune deficiency syndrome (AIDS) and as a rescue for tissue necrosis factor (TNF). Severe and unrelenting weight loss constitutes a prime risk factor in AIDS patients with Kaposi's sarcoma; in its capacity to reverse the cachectic state, hydrazine sulfate has been proposed as a treatment strategy for improving the nutritional status, and thus the clinical outcome, of these patients (47). TNF, a promising lymphokine with the ability to kill cancer cells, may be biochemically identical with cachectin, which is believed to trigger weight loss and body wasting in cancer, thus limiting this lymphokine's clinical potential. Addition of hydrazine sulfate has been suggested as a specific measure which could reverse this cachexia-inducing action as well as enhance, potentiate, or synergize TNF and result in a sizable anticancer effect (48).
With the advent of a specific anticachexia agent, more effective cancer control becomes possible. For the devastating aspects of this disease are due to two principal causes: invasion of tumor into vital organs with consequent destruction of their function; and decay of the body by virtue of cachexia and its resultant effect on the integrity of all body systems. Each of these processes has its own metabolic machinery, each is amenable to its own therapy, and each is to some degree functionally interdependent on the other. In the interest of treating the totality of malignant disease, each of these processes warrants intervention. Such an approach, dealing with both major underpinnings of the cancerous process -- mitogenic and metabolic -- affords the greatest promise for eliciting long-term, symptom-free survival and the potential for disease eradication.
Submitted 15 January 1986; accepted in final form 13 August 1986.
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