C. Chester Stock

Serum lipid‐bound sialic acid as a marker in breast cancer

The reliability of lipid‐bound sialic acid (LSA) as a marker in breast cancer was evaluated in 78 normal subjects, 106 patients with benign breast disease, 64 patients with primary operable breast cancer, and 61 patients with recurrent metastatic breast cancer. LSA levels were determined before and after mastectomy and during chemotherapy in selected patients to determine the value of LSA in monitoring therapy and predicting response. LSA levels greater than 20 mg/dl were not seen in normal subjects but were present in patients with benign breast disease (13%), primary breast cancer (47%) and recurrent metastatic breast cancer (62%). LSA levels decreased after initiation of chemotherapy and remained low in patients clinically disease‐free. Recurrences were associated with elevated LSA in patients failing chemotherapy or endocrine ablative surgery. LSA measurements appeared to be of limited value in the detection of breast cancer but serial measurements may be useful in assessing disease progression and identifying patients resistant to therapy. Cancer 50:1815‐1819, 1982.

Experimental cancer chemotherapy.

Publisher Summary Useful but not curative agents against cancer have been found. Steroids, carbamates, folic-acid analogs, nitrogen mustards, and related compounds are the most effective. While it can be anticipated that additional, active antifolic acids and nitrogen mustard-like compounds can be found, it is difficult to escape the impression that studies in all four categories of compounds have reached the point of diminishing returns as far as providing new compounds with superior degrees of effectiveness is concerned. Thus, any simple interference in a metabolic process common to tumors and normal tissue would be limited as a therapeutic procedure by the damage caused to the most sensitive normal tissues. The discovery by mouse and rat tests of substances useful in human cancer should provide an answer to the frequently raised question of whether results can be transferred from mouse to man. This chapter discusses test methods representative of those that have been used to find and study the antitumor activity of compounds.

Effects of N-Methylformamide and Related Compounds in Mouse Sarcoma 180.

Summary and Conclusions 1. Formamide and its more potent N-methyl derivative have been described as transient inhibitors of the growth of mouse sarcoma 180. This effect is not a property of formamides in general since other compounds containing the formamide moiety have failed to affect the growth of the tumor. 2. N-methylformamide has been shown to exert its effects when therapy is started either 24 or 96 hours after implantation of the tumor or when the agent is given in a single, large dose. Further, the compound has been found equally effective whether given by the oral or intraperitoneal route. 3. Histologic changes of a non-specific nature have been described in tumors from animals treated with N-methylformamide. 4. In view of the structural resemblance between formamide and urethane, the actions of both agents have been compared. Urethane, like formamide, inhibits the growth of S-180; however, treatment with the former substance causes toxic manifestations not encountered in mice given formamide. 5. Several conceivable mechanisms have been proposed to account for the inhibitory effects of the formamides. Further studies of these suggested modes of action may provide useful information concerning biochemical mechanisms involved in the growth of tumors. 6. In view of the hepatotoxicity of formamide and its N-methyl derivative it is not expected that these agents will prove therapeutically useful.

Chemotherapy of Leukemia. IV. Effect of Folic Acid Derivatives on Transplanted Mouse Leukemia.

Summary 1. Ninety compounds related to pteroylglutamic acid have been tested for chemo therapeutic effect against transmitted leukemia Ak 4 in mice. 2. Eighty-two of these compounds showed no chemo therapeutic effect by this particular technic. 3. Four showed slight to moderate effect. 4. Four compounds, 4-amino-N10-methyl-pteroylglutamic acid, 4-amino-9-methyl-pte-roylglutamic acid, 4-amino-9710-dimethyl-pteroylglutamic acid, and 2,6-diaminopurine have definite chemotherapeutic activity as demonstrated by approximately doubling the average survival time of the mice treated with these compounds. 5. The occurrence of an amino substitution in the second and fourth positions of the pyrimidine ring in all these active compounds has been noted.

Inhibition of development of sarcoma 180 by 4-amino-N10-methyl pteroylglutamic acid.

Summary The compound 4-Amino-N10-methyl pteroylglutamic acid, has shown the ability to inhibit the growth of the transplantable mouse Sarcoma 180 when administered intraperitoneally in concentrations of 1.5 mg/kg each day for 7 days. At this dosage very few mice died from drug toxicity. The inhibition is most apparent when the compound is administered early in the development of the tumor.

Effects of Certain Triazenes on Chick Embryos and on Tumors Explanted to the Chorioallantois.

Summary 1. A new compound that inhibits the growth of the sarcoma 180 in mice, 3,3 - dimethyl-1-phenyltriazene, “triazene,” also exhibits teratogenic activity in the chick embryo and damages mouse and human tumors explanted to the chorioallantois of the chick embryo. 2. The teratogenic syndrome produced by the injection of “triazene” into the yolk sac of the 4-day embryo consists of parrot-beak, micromelia, bent tibiotarsus, edema, and feather growth inhibition. This effect can be prevented by the injection of nicotinamide. Several analogs of “triazene” have been tested for teratogenic properties. 3. When injected into the yolk sac of embryos carrying chorioallantoic grafts of the mouse sarcoma 180 and Toolans human epidermoid carcinoma #3, “triazene” causes inhibition of tumor growth and cellular injury. This effect is similar to that produced by nitrogen mustard and other polyfunctional alkylating agents. Because “triazene” shows certain similarities in tumor-inhibiting activity when compared to nitrogen mustard and because of its distinctly different chemical structure, it warrants consideration as a candidate agent for clinical cancer chemotherapy.

Chemotherapy of Leukemia. V. Effects of 2,4,6-Triethylenimino-S-Triazine and Related Compounds on Transplanted Mouse Leukemia.

Summary 1. 42 compounds, of which 39 could be classed as triazines and 3 as ethylenimine ring compounds were screened for chemotherapeutic activity against Ak4 mouse leukemia. 2. 2,4,6-triethylenimino-s-triazine, 2,4-diethylenimino - 6 - amino - s - triazine, and hexamethylene diethylenurea significantly prolonged the survival time of mice injected with transplanted leukemia Ak4. 3. It would appear that the chemotherapeutic activity of the above compounds can be attributed to the ethylenimine structure. 4. Four other compounds containing either a triazine or an ethylenimine moiety showed a slight chemotherapeutic effect.

Asparaginase clearance, influence of the ldh-elevating virus.

Summary Asparaginase, injected in conventional therapeutic doses into mice previously inoculated with the lactate dehydrogenase-elevating virus (LDH-virus), disappeared from the peripheral blood at a significantly slower rate than in corresponding virus-free mice. Direct testing of the transplanted tumors and leukemias employed in the earlier studies on the antitumor properties of asparaginase have indicated that the virus, was unknowingly present. The evidence indicates that the virus, through its impairment of host enzyme clearance and possibly other factors, played a significant role in the observed therapeutic effects of EC-2 l-asparaginase against sensitive mouse leukemia and lymphosarcoma. We thank J. D. Loveless, M. A. Fitzmaurice, and Edith R. Shapiro for assistance.

An influence of 2,6-diaminopurine upon the content of kappa in Paramecium aurelia, variety 4.

Summary The content of effective kappa in Paramecium aurelia killers is markedly reduced by their exposure to 2,6-diaminopurine. This purine uniquely exhibits this capacity among the many purines and pyrimidines tested. The effect is blocked by the simultaneous presence of adenine, adenosine, or adenylic acid.

A Test of Triazolopyrimidines on Mouse Sarcoma 180.

Summary 8-Azaguanine and 4 other triazolopyrimidines at tolerated doses were without inhibitory effect on Sarcoma 180.