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Hypotensive action of a new dopamine beta-hydroxylase (DBH) inhibitor, 5-(4'-chlorobutyl)picolinic acid (FD-008) was investigated in dogs and rats. FD-008, which is one of the most potent inhibitors among fusaric acid derivatives, decreased blood pressure in spontaneously hypertensive rats relatively parallel to DBH inhibition in vitro. The effect of FD-008 on blood pressure was stronger in hypertensive rats than in normotensive rats. No cumulative effect was observed in rats by repeated administration, On the other hand, repeated administration was required to lower blood pressure in normotensive dogs. The acute effect of FD-008 on blood pressure of anesthetized dogs was somewhat different from that of its mother compound, fusaric acid.

During the course of screening of agents active in converting the transformed morphology of Rous sarcoma virus-infected rat kidney cells to the normal morphology, we identified an active substance produced by Streptomyces sp. MH237-CF8 as herbimycin. Herbimycin converted almost all cells into the normal morphology. The antibiotic was found to be an inhibitor of p60src-associated protein kinase in the cells.

Blcomycin (BLM) inhibits DNA and RNA synthesis in different isolated enzyme systems. The inhibition effect can be reduced by adcling RNA to the reaction mixture. The activity of the RNA dependent DNA polymerase and of a cell-free protein synthesizing system is not affected by BLM. The antibiotic reduces cell proliferation (L5178y mouse lymphoma cells) in vitro at low concentrations by cytostatis and at higher concentrations by cytotoxicity. In BLM-treated L5178y cells DNA synthesis is strongly reduced, while RNA and protein synthesis are not affected. In vivo , using growing quail oviducts, cell proliferation and cytodifferentiation are markedly inhibited after BLM treatment. This is attributed to the observed inhibition of DNA synthesis. RNA and protein synthesis as well as gene expression are not influenced by BLM under the conditions used.

Arphamenine A was synthesized in a cell-free system obtained from the arphamenine-producing strain, Chromobacterium violaceum BMG361-CF4. L-[14C]-phenylalanine was converted to beta-phenylpyruvic acid by phenylalanine amino-transferase obtained from the 10,000 x g supernatant (S10 fraction). [14C]-Benzylmalic acid was synthesized from beta-phenylpyruvic acid with [14C]-acetyl-CoA in the S10 fraction. [14C]-Benzylsuccinic acid was formed from beta-phenylpyruvic acid with [14C]-acetyl-CoA and ATP in this fraction, as was [14C]-arphamenine A from benzylsuccinic acid and L-[14C]-arginine. Thus, the pathway of arphamenine A biosynthesis was confirmed by the cell-free biosynthesis of this antibiotic.

The effect of a microbial protease inhibitor, leupeptin, on the induction of urinary bladder tumors in W rats by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Three groups of animals were given 0.01% BBN in their drinking water for 12 weeks. A basal powder diet supplemented with 0.1% leupeptin was given to group A throughout the experiment and to group B when BBN administration was stopped. Group C was given the basal diet without leupeptin throughout the study. The total preservation period was 40 weeks. Results clearly showed that when leupeptin was given during the promotion step of bladder carcinogenesis (as in group B), it increased the size of tumors and the incidences of cancer and invasion. When leupeptin was given throughout the experiments, its effect was counteracted (as in group A).

Oral administration of forphenicinol, S-2-(3-hydroxy-4-hydroxymethylphenyl)glycine, inhibited the growth of EL4 lymphoma by both pre- and posttreatment. Although some mice given this drug rejected the tumor, they could not obtain acquired immunity against the tumor. Macrophages taken from normal mice did not inhibit the growth of EL4 cells in vivo (tumor neutralization assay) or in vitro (cytostasis assay). Forphenicinol induced effector activity in such macrophages neither in vitro nor in vivo. Forphenicinol administration to mice bearing EL4 activated macrophages to inhibit the growth of EL4 in vitro and in vivo. Moreover, it stimulated the tumor growth-inhibitory activity of splenocytes in both tumor-free and tumor-bearing mice.

The authors have synthesized 7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl) adriamycinone (FT-ADM) which exhibited strong antitumour activity and weak toxicity. These characteristics of FT-ADM are partly due to the presence of a 2'-fluoro atom which strengthens the glycoside bond. FT-ADM, however, is sparingly soluble in water because of lack of the 3'-amino group of adriamycin. To increase the solubility of FT-ADM, a hydrophilic group was added at the 14-OH group. Then, the 14-hemisuccinate, 14-hemiglutarate, 14-hemiadipiate, 14-hemipimelate and 14-hemisuberate derivatives of FT-ADM were synthesized. Among them, the 14-hemipimelate derivative (FAD-104) was selected for further development because of its potent antitumour activity and weak toxicity. When drugs were injected intraperitoneally every day from day 1 to 9, FAD-104 showed an apparently stronger antitumour effect against mouse L-1210 leukaemia than adriamycin with lower toxicities. FAD-104 was also more effective than adriamycin on L-1210 using other administration schedules. A characteristic feature is that FAD-104 is effective over a very broad range, which will be advantageous for safe clinical use. FAD-104 also showed marked antitumour effect against L-1210 when it was injected intravenously either once on day 1 or three times on days 1, 5 and 9. Thus, FAD-104 may be a more potent antitumour anthracycline than adriamycin.

Biological effect of bestatin in combination with bleomycin against rat ascites hepatoma AH 66 was investigated. The combined use of bestatin and bleomycin both at a dose of 0.5 mg/kg was found to have a strong inhibition of the tumor growth. The combined effect was also confirmed histologically as follows. In combination group, increase of necrobiosis area in the tumor lesion, augmentation of infiltration of lymphocytes and macrophages around the solid tumors, and marked replacement of necrotic area by fibrous granular lesion were stronger and more rapidly than that in the other group.

We followed the time course of the activities of various hydrolytic enzymes in murine brain for 30 months to investigate their roles in the aging process. Although most of the 15 enzymatic activities tested tended to rise with the increase in age, by analyzing them by multivariate analysis their movements could be divided into three types, each having a particular mode of nonlinear regression: exponential, logarithmic, or parabolic. Several enzymatic activities, including those of angiotensin-converting enzyme, esterase, trypsin-like enzyme, post-proline-cleaving enzyme, and Gly-Pro-aminopeptidase, showed rhythmic oscillations with about one cycle per 3 months throughout the period of 30 months. The behavior of these enzymes probably represents some particular aspect of metabolism relatively independent from the aging process. These findings may provide a fundamental clue in association with the process of maturation and aging in the brain.

The effect of six protease inhibitors, isolated from various species of actinomycetes, on focus formation by murine sarcoma virus was examined. Pepstatin was the only inhibitor. The treatment of cells with pepstatin at various times possibly retards the early stage of infection with murine sarcoma virus.

The kanamycin inactivating enzyme, 3'-phosphotransferase and 6'-acetyltransferase were first found in 1967 and on the basis of the enzymic mechanism of resistance a new research approach to the development of active useful derivatives was explored. The enzymic mechanism of resistance was conclusively confirmed by the synthesis of 3'-deoxykanamycin A and 3',4'-dideoxykanamycin B which did not undergo inactivation by 3'-phosphotransferase and inhibited the growth of resistant strains. Besides APH(3') and AAC(6') described above, the following enzymes were found to be involved in the mechanism of resistance to aminoglycosides: APH(3''), APH(5''), APH(6), APH(2''), AAC(3), AAC(2'), AAD(3''), AAD(2''), AAD(4'), AAD(6). Not only the removal of the group which undergoes the enzyme reaction but also the modification of the group binding to the enzyme has also given active derivatives such as amikacin etc. The substrate specificity of the enzymes, enzymes in the immobilized state, and the application of proton and 13C nmr for structure determination of reaction products are reviewed. It was noticed that all enzymes involved in resistance contain adenosine- and aminoglycoside-binding sites. These enzymes were thus suggested to be mainly different primarily in the positional relationships between these binding sites. It suggests a close evolutionary relationships of these enzymes. The role of these enzymes in the biosynthesis of aminoglycoside antibiotics is discussed and a general mode of the biosynthesis of aminoglycosides is proposed: a gene or gene set involved in biosynthesis of 2-deoxystreptamine which has no cytotoxicity is widely distributed and the deoxystreptamine produced is transformed to the final products.

Serum levels of various hydrolytic enzymes in prostatic cancer patients with or without bone metastasis were compared with those in patients with prostatic hypertrophy and in the control subjects. The enzymes tested included 11 aminopeptidases, 2 endopeptidases, dipeptidyl carboxypeptidase, esterase, acetyl cholinesterase, and RNase. Although most of the enzymatic levels tended to be decreased in the cancer patients without bone metastasis, they tended to be increased in those with metastasis as well as in the patients with prostatic hypertrophy. Thus, bone metastasis is an important factor affecting the serum levels of hydrolytic enzymes in cancer patients. Of the enzymes tested, RNase was unique in that its serum levels were significantly increased regardless of the existence of bone metastasis. This enzyme may become a marker of malignancy.

The present study was undertaken to compare the enzymatic oscillations induced in three major organs, spleen, kidney, and liver, of mice by the active and inactive forms of an aminopeptidase inhibitor, bestatin. Although bestatin caused sine curve-type oscillations of enzymatic activities in spleen and kidney, its isomer, possessing no enzyme-inhibiting actions and no biological actions, did not show any typical enzymatic changes. Such typical oscillations were not elicited by either one of those two agents in liver, in spite of the apparent difference in the type of oscillations induced by them in this organ. These observations were taken to indicate that the enzymatic oscillations in vivo caused by bestatin are closely related to its aminopeptidase-inhibiting actions seen in vitro and that the immunomodifying actions of this agent are based on its effects on enzymes sensitive to it, possibly involving immunoresponsive cells.

Gewebe enthalten ein Enzym, das Bleomycin (BLM) inaktiviert. Die Enzymaktivitat ist in Extrakten aus verschiedenen Geweben unterschiedlich hoch. In der vorliegenden Arbeit wird eine Methode zur Bestimmung der BLM-inaktivierenden Enzymaktivitat aus Organen und Geweben von Mausen beschrieben. Diese BLM-inaktivierende Enzymaktivitat ist in Extrakten aus Leber am hochsten, Hoden, Milz, Lunge und Gehirn weisen geringere Aktivitaten auf; in Hautgewebe fehlt dieses Enzym fast vollig.

The pharmacokinetics and physiological disposition of a novel anthracyclines, (2''R)-4'-O-tetrahydropyranyladriamycin (THP) were studied in dogs by an HPLC analysis. The THP administered intravenously (1.5 mg/kg) disappeared rapidly from the plasma immediately after an injection of the drug. The plasma level of THP was lowered in a triphasic pattern up to 24 hours and was simulated by a three-compartment open model in which the half-lives of alpha-, beta- and gamma-phase were calculated to be 0.0116 hour, 0.152 hour and 7.02 hours, respectively. The blood cell level of THP was about 10 times as high as the plasma level during the observation. In the study of tissue distribution of THP 2 and 8 hours after the administration, the highest concentration of THP was found in the spleen and lung and these concentrations were diminished quickly. However, in the lymph nodes and bone marrow concentrations of THP increased with a lapse of time. THP and its metabolites were excreted in the bile by 2.7% of dose during 8 hours in the bile-cannulated dogs. Urinary recovery of THP and its metabolites was about 1.3% of the dose up to 72 hours. In these experiment, THP was metabolized to THP-OH and ADM, and to aglycones which were excreted in conjugated forms. The results obtained from a similar study on ADM were compared and discussed.

Recently, attentions are being aroused as to the enzymatic network abnormalities lying behind congenital enzyme deficiency syndromes. We investigated abnormalities in activities of various hydrolytic enzymes in serum of patients with congenital adrenal hyperplasia (CAH, 21-hydroxylase deficiency). Several enzyme activities including trypsin-like enzyme, cathepsin C and esterase were significantly decreased in patients' serum. Especially the esterase activity in patients' serum was reduced to one third of controls and this may have some relations to the abnormal steroid metabolism of these patients. A multivariate analysis showed unexpectedly extensive abnormalities in enzyme interrelationships. These results suggest that wide variety of abnormal metabolism may be related to an apparent enzyme deficiency.

An effective treatment schedule with bleomycin in combination with mitomycin and a new effective area in treatment with neocarzinostatin was introduced. Studies on more useful derivatives or analogues of bleomycin and anthracycline antitumor antibiotics were described. Bleomycin PEP thus selected may become a useful agent. Aclacinomycin and various other anthracycline glycosides were isolated from beer fermentation and tested. Future progress in microbiol secondary metabolites useful in cancer treatment was discussed.

In order to know the role of hydrolytic enzymes in various immunological disturbances, we compared the enzymatic changes in the spleens of nude mice and NZB/W mice relative to their respective controls. In spite of the different immunological features of these models, multivariate analysis demonstrated that there is some commonness in enzymatic changes between the two models. The enzymes related to such commonness included glycosidases, alkaline phosphatase, fMet-AP, and esterase. These enzymes may play some important roles in immunologic dysregulation , especially in relation to B-cell dominance in these disease models.

Antibiotics and small molecular enzyme inhibitors produced by micro-organisms are microbial secondary metabolites which have no obvious function in the growth of microorganisms. Involvement of plasmids in their biosyntheses has been studied and the structure of the microbial world where various compounds with widely varying structures have been found has been shown to be due to the presence of a great variety of plasmids. On the basis of this structure of microbial world, the author has found the microbial products which have various activities useful in treatment of cancer or in suppression of carcinogenesis. In this paper, the author reviewed his following studies: the plasmid involvement in biosyntheses of bioactive microbial secondary metabolites; the mechanism of therapeutic effect of bleomycin, and the development of useful analogs and derivatives of bleomycin and anthracyclic antibiotics; the screening method to find compounds affecting immune system, and the action of bestatin in enhancing delayed-type hypersensitivity and therapeutic effects of anticancer agents; enzyme inhibitors with potential utility in treatment or prevention of cancer.

The activities of various hydrolytic enzymes in splenic tissues of nude mice were compared with those of their controls of the same age. Since all of the enzymatic activities varied with age in both nude mice and in the controls, the difference between the two groups were difficult to define clearly. Principal component analysis enabled us to clearly categorize the enzymatic variations of both groups into two main components. One was related to the maturation process of the animals and the other to the pathological processes in the nude mice. The enzymes related especially to the latter component were formyl-methionine aminopeptidase (fMet-AP), mannosidase, and beta-N-acetyl-D-glucosaminidase (GlcNAc-ase). These enzymes may represent the abnormality of the surface of lymphocytes in the nude mice.

The biosynthetic pathway of an unusual amino acyl [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl (AHP)] moiety which is contained in bestatin has been studied by testing the incorporation of potential precursors. L-[U-14C]-Phenylalanine, L-[U-14C]leucine, and [U-14C]acetic acid were efficiently incorporated into bestatin, but the radioactivity of L-[1-14C]phenylalanine, [1-14C]glyoxylic acid, and [14C]oxalic acid were not incorporated. Incorporation of acetic acid into 1- and 2-carbon of the AHP moiety was confirmed by incorporation of [13C]acetic acid. Thus, the AHP moiety was shown to be biosynthesized from L-phenylalanine and two carbon atoms of acetic acid, accompanied by decarboxylation of the phenylalanine.

Limitless numbers of various genetic structures have been formed in chromosomes and plasmids and numerous bioactive compounds are produced by microorganisms. Therefore, it may be said that compounds useful in treatment of cancer will be found more and more in microbial secondary metabolites and more effective antitumor antibiotics and their derivatives, or more effective products producing immune resistance to cancer, will be discovered. In these studies, as discussed in this paper, the most urgent problem is to establish a rational screening principle or system to select compounds worth clinical examination. This is particularly important in the analog area. Bleomycin is an analog of phleomycin chosen because of lower renal toxicity. It has become an antitumor agent of significant value. Macromycin is a new structure which has been found to bind with animal cells and inhibit growth. Neothramycin is a new benzodiazepine antibiotic which has lower toxicity than other structures studied in this class and is active against L1210, Yoshida sarcoma, and Sarcoma 180. Aclacinomycin A is an analog of adriamycin chosen for clinical study based on its low cardiac toxicity and high distribution in mouse lung and spleen. Coriolins are another new structural class. Diketocoriolin B has activity in L1210 leukemia and has been shown to inhibit Na-K-ATPase. Bestatin is a compound which inhibits aminopeptidase B and leucine aminopeptidase has been shown to increase delayed hypersensitivity. Bestatin also increases the effects of other antitumor agents such as adriamycin, and bleomycin.

Studies of microbial secondary metabolites are being continued for the purpose of finding compounds useful in the treatment of curing cancer. Derivatives and analogs which have lower characteristic toxicities of parent antitumor antibiotics such as adriamycin, bleomycin, mitomycin, etc. are being developed. The mechanism of therapeutic action and chemical synthesis have contributed to the development of new useful bleomycins. New screening methods have always been studied and new types of interesting antitumor antibiotics such as bactobolin, oxanosine, spergualin, etc. have recently been discovered. The research area of antitumor antibiotics has been expanded to low molecular weight immunity-enhancing compounds, and bestatin, forphenicinol, arphamenine, etc. have been discovered. The effects of bestatin on human and mouse immunity systems have been studied in detail. Moreover, the study of microbial products which inhibit the generation of suppressor cells has recently been started. Oxanosine, bestatin, forphenicinol, arphamenine, etc inhibit the generation of suppressor cells. Oxanosine has strong activity. The treatment with the combination of the compounds described above will contribute to the increase of the rate of cancer cure. In this paper, the studies by H. Umezawa and his collaborators are described.

An antibody against aclacinomycin A (ACM) was produced in a rabbit by immunization with ACM-bovine serum albumin conjugate. The radioimmunoassay (RIA) was based on the competition of unlabeled anthracycline with 3H-labeled ACM for binding sites on a specific antibody. Antibody-bound and free antigen were separated by selective adsorption on dextran-coated charcoal. The antibody reacted equally with ACM and its metabolites, MA144 M1, MA144 S1 and aklavin, and could precisely distinguish aklavinone-related aglycones, adriamycin and daunomycin. RIA was sensitive in the range of 1 approximately 10 pmol per assay. The quantities of ACM and its metabolites in human plasma were practically determined without any pretreatment of physiological samples.

The structures of bleomycins, including their stereochemistry as shown in Figure 1, were conclusively determined by a study in the author’s institute in 1978 (Takita, Muraoka, Nakatani, Fujii, Umezawa, Naganawa & Umezawa, 1978b). The N-terminal amino acid contained in the bleomycin molecule was called pyrimidoblamic acid. Demethylpyrimidoblamylhistidylalanine which was thought to be a biosynthetic intermediate was isolated from a culture filtrate of a bleomycin-producing strain and its copper complex was crystallized. The structure of bleomycin shown in Figure 1 has been supported by crystal X-ray analysis and also by the chemical synthesis of pyrimidoblamic acid. Moreover, this structure has been confirmed by 15N-n.m.r. of bleomycin A2 (Naganawa, Takita, Umezawa & Hull, 1979) and also by mass spectroscopic analysis of bleomycins Bľ which gave the exact molecular weight of bleomycin (Macfarlane, Fujii, Takita & Umezawa, 1980). The main structural group common to all bleomycins is called bleomycinic acid (Figure 1). Bleomycinic acid consists of a peptide moiety, pyrimidoblamyl-β — hydroxy-histidyl- (4-amino-3-hydroxy-2-methyl) pentanoyl-thereonyl-2′- (2-aminoethyl)-2,4′-bithiazole-4-carboxylic acid, and a disaccharide part, 2-o-(3-o-carbamoyl-d-mannopyranosyl) -l-gulopyranoside. Bleomycin consists of bleomycinic acid and a terminal amine. As shown in Figure 1, various bleomycins which are different from one another in the terminal amine are produced by a bleomycin-producing strain. The present bleomycin used clinically consists mainly of bleomycins A2 and B2.

A method was developed for the isolation of cathepsin D by affinity chromatography on immobilized pepstatin. This inhibitor was coupled to agarose by water soluble carbodiimide. Further purification included gel filtration on Sephadex G-100. The obtained cathepsin D exists in three active forms which were resolved on DEAE cellulose. Electrophoresis in the presence of sodium. dodecyl sulphate revealed that the first form consists of only one polypeptide chain having molecular weight 42 000. The second and the third form contain also polypeptides having molecular weight 27 000 and 14 000.

A study was performed to elucidate the effects of low-molecular-weight enzyme inhibitors on enzyme networks in vivo. Seven compounds, including bestatin and its 5 derivatives and arphamenine B, were tested, with each of them being administered to mice at the dose of 200 micrograms/day for 8 consecutive days. The spectrum of enzymatic changes thus induced were extensive and were not simply explainable by the in vitro actions of each agent administered. Nevertheless, a multivariate study on the changes in enzyme networks showed some degree of interrelationship between the in vitro and in vivo actions of the agents under study. The present findings seem to certify that the direct enzyme-inhibiting effect motivates the extensive movement of enzyme networks in vivo, although the latter often seems rather paradoxical at a glance.

Acute toxicity to the hematopoietic cell renewal system is a critical side effect of most anticancer agents. Here we compared the effects of FAD-104 to those of the parent compound adriamycin (ADM) and of epi-adriamycin (epi-ADM) on the growth and differentiation of normal as well as leukemic human myeloid progenitor cells. FAD-104 was less toxic to myeloid colony-forming cells (GM-CFU) than ADM or epi-ADM. In addition, FAD-104 but not ADM induced a clonal down-grading in both normal and leukemic blast cells, and it stimulated the terminal differentiation of myeloid leukemia cells. Therefore, FAD-104 may be useful in the treatment of some forms of myeloid leukemia.

The resistance of Staphylococcus aureus MS-9610 to tylosin and 3-O-acetyltylosin was due to the decreased affinity of its ribosome system to these macrolides. However, 3-O-acetyl-4''-3-O-isovaleryltylosin was found to bind to ribosomes of the strain about three times more than 3-O-acetyltylosin. This binding was not interfered by tylosin and 3-O-acetyltylosin. The 4''-O-acyl group and the mycinose moiety were suggested to have an important role in the binding of tylosin derivatives to ribosomes of resistant strains.

Previous studies indicated a relationship between immune deficiencies and abnormalities in the activities of various hydrolytic enzymes, including proteinases, in tissues. In the present study, we compared such activities in spleen among the three types of murine models of systemic lupus erythematodes (SLE) (i.e., New Zealand black/white mouse, MRL mouse, and BXSB mouse) and their controls. According to the results of multivariate analysis, it was shown that the most important enzymatic changes differentiating the pathologic animals from their controls were decreases in the activities of serine proteinases. Judging from the behavior of these enzymes in various immunological disturbances, it is likely that they play some important roles in pathophysiology of SLE.

In order to understand the effects of an immunomodulator in vivo, we performed time series analysis on mice given an aminopeptidase inhibitor, bestatin. This agent, which is known to be an immunopotentiator, caused peculiar oscillation of the activities of various hydrolytic enzymes in spleen. Autocorrelation curves obtained from serial data of each enzymatic activity revealed that sine curve-type oscillations are brought about in enzyme networks by this inhibitor. Judging from the pattern of the variations of enzymatic activities, it seems that metabolic homeostasis is strongly affected by this agent. The inhibitor probably initiated the homeostatic movements directly and secondarily caused extensive changes in the enzyme networks in vivo. This effect of bestatin may be useful in altering the pathological homeostasis (such as the one in autoimmune diseases) by affecting the dynamic equilibrium among the various components in the immunological system.

We examined if superoxide anions would be produced when bleomycin-Cu (II) were incubated with cysteine under an aerobic condition. Strong reductions of cytochrome c and nitroblue tetrazolium chloride were observed when 0.065 mM bleomycin-Cu (II) and 0.1 mM cysteine were incubated. Neocuproine, which binds specifically with Cu (I), inhibited the reduction of both agents, while superoxide dismutase inhibited only the reduction of nitroblue tetrazolium chloride. These results suggest that cytochrome c is directly reduced by the cuprous ion released from bleomycin-Cu (II) in a reducing reaction with cysteine and nitroblue tetrazolium chloride is reduced by the superoxide anion formed in the reaction of the cuprous ion with oxygen.

Oral administration of forphenicinol stimulated the production of lipopolysaccharide (LPS)-induced interferon (IFN) in mice up to 21-fold over control when given more than 10 days before the elicitation. The IFN production in mice sensitized with bacillus Calmette-Guerin (BCG) 14 days before LPS injection was further augmented by forphenicinol given after BCG. In addition to the IFN production, forphenicinol increased production of LPS-induced tumor necrosis factor (TNF) in mice sensitized with BCG, and the dose of LPS required to induce TNF was reduced by the drug. Furthermore, forphenicinol augmented the antitumor effect of BCG and LPS on Meth A fibrosarcoma.

THP-ADM is a new anthracycline with broad antitumor activity without cardiac toxicity or alopecia in experimental models. Phase I studies had established a proposed dose for phase II trials of 50 mg/m2 every three weeks. This modality gave an insignificant result in breast carcinoma. Cellular pharmacokinetics suggested that a longer time of administration could be more efficient. In this phase II trial oriented to advanced breast cancer, we have used 3 consecutive daily doses of 20 mg/m2/day in monthly cycles with dose escalation in each patient. We have observed 28% partial remissions (PR). Two patients previously treated with adriamycin had PR. Significantly less alopecia and no cardiac toxicity were observed.

Antitumor antibiotics research has made great progress both in the development of new types of antitumor cytotoxic compounds with potential usefulness and in the development of effective derivatives and analogs of already proven compounds such as doxorubicin, bleomycin, and mitomycin. Such research has also been expanded to include the study of low molecular weight enzyme inhibitors and immunomodifiers of microbial origin, which, with their derivatives and analogs, can also be expected to increase the cure rate for cancer. Recent results of research to discover and learn about these compounds are described here, after a brief historical introduction.