In our laboratory, we have studied the mechanism of action of
tumor-inhibitory
antibiotics, including
bleomycin,
phleomycin,
adriamycin,
aclarubicin, neothramycin, macromomycin,
auromomycin,
chartreusin,
pluramycin, neopluramycin,
xanthomycin A, angustmycins A and C,
blasticidin S and
phenomycin. The recent advances are summarized. Screening of microorganism for new antitumor
antibiotics based upon our studies on mechanism of action are currently ongoing. We are interested in drug-resistance of
tumor cells, and have obtained
drug-resistant sublines of murine lymphoblastoma L5178Y cells. We have found that
glycoprotein synthesis and
alkaline phosphodiesterase (APD) activity of the plasma membrane are higher in
adriamycin (ADM)-,
aclarubicin (ACR)- and
bleomycin (BLM)-resistant cell sublines than in the parental cells. An inhibitor of APD has been isolated from a soil Streptomyces, and identified with 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone (
COTC).
COTC inhibits growth of the
drug-resistant cells more significantly than the parental cells, and exhibits synergistic activity with ACR against ACR-resistant cells.
COTC is a SH inhibitor. Although
COTC is a multifunctional
drug, the inhibition of
DNA polymerase alpha and some mitotic process may be related to its lethal action. In the course of our screening, we have found that a strain of Sterptomyces hygroscopicus produces two substances: one inhibits
thymidine and
uridine uptake of human leukemic K562 cells, and the other stimulates it. The inhibiting substance has been identified with
tubercidin, and the stimulating one has been found to be a novel pyrrolo [2,3-d]
pyrimidine antibiotic,
cadeguomycin.
Cadeguomycin shows low acute toxicity in mice, enhances DTH reaction, and inhibits Ehrlich ascitic
carcinoma in mice. The
antibiotic exhibits synergistic effects with
arabinosylcytosine against growth of K562 cells. Saframycin, discovered by Prof. Arai, Chiba University, is effective against Ehrlich ascitic
carcinoma, P388 and
L1210 leukemia, and
B16 melanoma in mice. The target is
DNA.
Stubomycin, discovered by Dr. Umezawa, Kitasato Institute, is effective against
Sarcoma 180, Ehrlich
carcinoma,
P388 leukemia, IMC
carcinoma and Meth-A
tumor in mice, and shows low acute toxicity. The target is plasma membrane.