Pattern analysis of microtubule-polymerizing and -depolymerizing agent combinations as cancer chemotherapies.
Subcellular distribution of mass can be analyzed by a technique that involves culturing cells on interferometers and digitizing their interference contours. Contour sampling resulted in 102 variables per cell, which were predictors of oncogenic transformation. Cell phenotypes can be deconstructed by use of latent factors, which represent the covariance of the real variables. The reversal of the cancer-type phenotype by a combination of microtubule-stabilizing and -depolymerizing agents was described previously. The implications of these results have been explored by clinicians who treated patients with the combination of docetaxel and vinorelbine (Navelbine). The current study was performed to determine the effects of different combinations on phenotype and in phases of the cell cycle other than mitosis. Combinations of paclitaxel with either colchicine, podophyllotoxin, nocodazole, or vinblastine caused phenotype reversal. Paclitaxel analogue, 7-deoxytaxol, by itself caused reversal. Factors #4, (filopodia), #5 (displacement and/or deep invaginations in the periphery), #8, and #12 took on values typical of normal cells, whereas the values of #7 (p21-activated kinase), and #13 (rounding up) shifted toward the cancer-type. All combinations altered microtubule arrangement at the cell edge. Delivery schedules and drug ratios used in clinical studies were subjected to analysis. Clinical response rates were better when the combination was not interspersed with a single agent (P=0.004). The results support the idea that efficacy depends upon simultaneous exposure to both agents, and suggest a novel mechanism for combination therapies. These therapies appear to restore in transformed cells some of the features of a contact-inhibited cell, and to impede progress through the cell cycle even when provided at nanomolar concentrations.
Uppal
S O
SO
Department of Biological Sciences, Bowling Green State University, Bowling Green, OH 43403, USA.
Li
Y
Y
Wendt
E
E
Cayer
M L
ML
Barnes
J
J
Conway
D
D
Boudreau
N
N
Heckman
C A
CA
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D002986:Clinical Trials as Topic; D003078:Colchicine / Q000008:administration & dosage; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010641:Phenotype; D051381:Rats; D011919:Rats, Inbred Strains; D050257:Tubulin Modulators / Q000008:administration & dosage*
D050257:Tubulin Modulators; D017239:Paclitaxel; D003078:Colchicine