Antitumor activity of locally-isolated actinomycins

The actinomycins were isolated from two locally-grown Streptomyces cultures S-67-3 and S-62-30. Acute and short-term toxicity studies on S-67-3 using mice, rats, rabbits and monkeys showed much less toxicity than S-62-30. The LD50 of S-62-30 in mice was 1.78 mg/kg by subcutaneous route. In rats, the LD50 by intraperitoneal route were 0.095 mg/kg and 0.1 mg/kg for S-62-30 and S-67-3, respectively. Toxicities of the two fractions, however differ significantly below and above the LD50. While a dose of 1 ug/kg of the S-62-30 fraction proved very toxic to monkeys. S-67-3 showed hardly any toxicity at the same dose level. A dose of 5 ug/kg of S-62-30 was lethal to the two monkeys tested. S-67-3 showed barely any marked acute toxicity on the rabbits up to 1.0 mg /kgPreliminary studies in vitro showed significant activity against ascitic tumors, TB bacillus and Gram-positive bacteria. In vivo studies on three types of experimental tumors showed inhibition of Ehrlich Ascites Carcinomas (EAT) in Swiss albino and Leukemia L-1210 in DBA/2 and BDF, mice but not Sarcoma (S-180) in either C57 or the local strain of white mice. The Sarcoma regressed in both control and experimental groups with necrosis and alopecia at the site inoculation. Such apparent "immunity" was not observed with EAT or L-1210. Marked inhibition of L-1210 was observed with S-67-3 when grown in DBA/2 or BDF, mice, at a dose of level of 20 ug/kg and higher. Dose-response curves on S-67-3 reveal a higher antitumor activity and a lower toxicity as compared with S-62-30 which is rather unusual for cytotoxic agents. Implications in therapy are discussedSignificant alteration in tumor membrane phospholipoprotein was observed at the higher dose levels (20 ug/kg and 40 ug/kg) as assessed by thin-layer-chromatography. Such effects are extrapolated to have produced changes in membrane permeabilityThe role of cyclic-adenyl cyclase system in membranes in relation to "contact inhibition" is also discussed with projections into wound healing, embryogenesis, differentiation, aging and cancerSo far, pharcogenetic studies on mice, rats, rabbits and monkeys now in progress (except on monkeys which was temporarily suspended) have not shown significant results for meaningful evaluation. Studies on the possible immunosuppressive activity are now underway.(Summary)

Sex difference in response to a carcinostatic agent aristolochic acid

Toxicity and tumor studies were done with a local medicinal plant alkaloid, aristolochic acid against Ehrlich Ascites Carcinoma in mice. A striking and consistent sex difference in response, both in toxicity and antitumor activity was observed. There was at least a dual effect on males and females as regards toxicity, depending on whether the drug was given in acute single doses or in short or long-term chronic regimens. With acute doses, males were found more susceptible to the drug. Conversely, the females were more affected by chronically administered drug. The cause/s of death in either case may not be the sameAt dose levels below the ED50 (1.15 mg/kg), it showed higher antitumor activity in males compared to the females. At higher doses beyong the ED50, the reverse is true, females more than malesThe possible role of sex hormones in regulating membrane permeability, which is believed to be altered in carcinogenesis is emphasized. The significant relationship of biochemical structure, that is lipids, proteins and carbohydrate residues, to membrane permeability, is also discussed. Investigations, both at the gross and biochemical level confirm its antineoplastic activity. Marked renal and hepatotoxicity, however, are risks one has to contend with should it be used in clinical cancer chemotherapy. (Summary)

Prolonged corticosteroid therapy of a collagen disease with intermittent ACTH and antimalarial regimen

The case is unusual because of long remission of fifteen years despite the manifestations of both forms of Lupus Erythematosus, i.e., Discoid (DLE) and the Systemic or Disseminated (SLE). Usual prognosis is five yearsSubacute attacks usually precipitate whenever there is a lapse in drug schedule and diet, especially with regard to sodium intake. Dangers from such indifference and overoptimism can be great. Extreme anxiety and frequent tensions, undue exposure to extreme temperature, radiation and pathogens can precipitate attacks of ischaemia and bacteremia which can prove difficult to control. Moreover, prolonged antibiotic therapy can lead to the development of resistance and superinfection which can prove fatal. Osteoporosis can lead to spontaneous fractures. Development of fulminant ulcers demands strict antacids and anti-ulcer therapyUnless the patient is given detailed instructions and made to understand the importance of strict adherence to therapeutic regimen with ability to modify such diseases have no "cure," the variable situation he is subjected to, close medical supervision and frequent check-ups are simply imperative. The important role played by the right attitude on the part of the patient is highly emphasized, considering that such schedule to meet the demands of bilitating and life-threatening, and can even be acutely fatal. (Summary)

Choline deficiency and HC 3 action: possible implication in tumor induction

The acetycholine-cholinesterase sytem has often been implicated in the regulation of transport across biological membranes. Drugs affecting such systems are, therefore, of much interest to most investigators in this field and one of these is Hemicholinium No. 3, otherwise known as "HC3"HC-3 has been known to produce marked respiratory paralysis, possibly due to inhibition of acetylcholine systnesis through a block in choline transport across nerve membranes. The role of choline in lipid metabolism and in nervous transmission has been well established. Any alterations in the choline transport may, therefore, manifest in some derangement in the biochemical reactions involving such mechanisms, eventually leading to a disturbance in function. Moreover, any drug inhibiting such transport mechanism, may be expected to manifest signs to choline deficiency

Effect of variation in medium on chloroquine inhibition of pigment production by serratia marcescens

Chloroquine Diphosphate (ARALEN) was found to inhibit the biosynthesis of a red pigment, Prodigiosin, by Serratia marcescens, Strain NIMA. Pigment production in two other strains, a PTR-treated orange variant (PTR-O) and a streptomycin-resistant mutant (Sm-Pow), were also inhibited without inhibiting growth. A similar effect has been observed with phosphate alone. In order to separate the drug effect from that of the phosphate alone, inhibition studies were tried on non-growing cultures. Phosphate alone did not affect pigment production by the Strain NIMA in a non-proliferating system using 2 DL-alanine medium. The diphosphate salt produced inhibition in both growing cultures and the non-proliferating system. Inhibition by the base and a hydroxy-derivative of the drug in nutrient agar medium further supports the above hypothesis. The precise mechanism of inhibition by either, however, remains unknown. Possibilities for the finer mechanism/s involved in these inhibitions are discussedThe reciprocal effects in nutrient agar and peptone-glycerol agar medium in the case of the base and the hydroxy-derivative as compared with the phosphate alone, however, was not observed in the case of the diphosphate salt. The role of metal chelation and pH variation is mentioned as possible explanation for variation in results obtained in solid media. Extrapolation of these effects to the efficacy of the drug in some collagen diseases is also discussed. (Summary)